EP orals

[JRotten]

Interested in reviews on the halo, m1t, and dbol. Halo and dbol are two of my favorite aas of all time and m1t just sounds interesting.

Who's tried them?

 

[Trentmeister4530]

Bro I'm intrigued in this as well since aap...


Sent from my iPhone using Tapatalk

 

[Brendanj9554]

The only oral I have had from EP is dbol (10mg/100) In all honesty I got absolutly nothing from them on two occasions nearly a year apart.

Never had had an issue with there oils, just oral.

But I don't seem to have much luck with Orals, that's why I have ordered raws to do my own liquid oral.

Never tried halo or m1t from any lab. But if I find a good source I may have a try in the future

 

[ldog]

Bros,

Diesel Jimmy has a thread on our Halo. As far as the Dbol, I've heard nothing but great things. Please try it for yourself and let us know. Reach out to V as well so he can add his two cents. My personal feedback is that there is no difference in quality between the orals and oils.

 

[Vision]

The only oral I have had from EP is dbol (10mg/100) In all honesty I got absolutly nothing from them on two occasions nearly a year apart.

Never had had an issue with there oils, just oral.

But I don't seem to have much luck with Orals, that's why I have ordered raws to do my own liquid oral.

Never tried halo or m1t from any lab. But if I find a good source I may have a try in the future

This is very unfortunate, you sound like a nonresponder (they are out there, and its with most medications).. I would suggest taking grapefruit juice next time with your oral cocktail that you make, it will assist with absorption and drug bioavailability I'll include a study below.

To the OP I know you do NOT wish to hear from a rep and you seek info from MEMBERS,but, you know how unbiased I am, I have dbol,drol and adex here, I'm starting THIS WEEK.. I will let you know.. I can't stand down wind from dbol without lactating (adex/tamox on hand) plus I respond very well to drol and dbol,I just wish I was growing with age because my time is becoming limited
So I will update you either way.. You may beat me to the M1T if you decide to get it,because I have none, but the dbol/drol I'll have a reply for you soon enough

Im beyond confident in what I have in my hands

 

[Vision]

The only oral I have had from EP is dbol (10mg/100) In all honesty I got absolutly nothing from them on two occasions nearly a year apart.

Never had had an issue with there oils, just oral.

But I don't seem to have much luck with Orals, that's why I have ordered raws to do my own liquid oral.

Never tried halo or m1t from any lab. But if I find a good source I may have a try in the future

Increase potency oral steroids ( grapefruit juice increase the bioavailability )

Visions addition to a cheap and cost effect method to help increase the potency and bioavailability of oral steroids.

For sometime now I've known about this practice,and heard amazing results from people utilizing this protocol, with exceptional results.. I to have used this method and seen/felt pronounced effects with the oral I was taking..With low dosages,warning though, this can lead to liver toxicity levels if abused!
This method is also commonly used in the manufacturing process of some pro-hormones, with grapefruit exact added to the binders/fillers!

Grapefruit extract or juice also has a this pronounced effect with medications and YES including steroids!

Grapefruit juice will increase the potency of most oral drugs including steroids here is the article and a blind study

Study-

Ceska Gynekol. 2003 Mar;68(2):117-21.
[Does grapefruit juice increase the bioavailability of orally administered sex steroids?].

[Article in Czech]
Fingerov? H, Oborn? I, Petrov? P, Bud?kov? M, Jezd?nsk? J.
Source

Klinika porodnictv? a gynekologie LF UP v Olomouci.

Abstract

OBJECTIVE:

To verify if and to which extent the interaction with grapefruit juice can increase bioavailability of orally administered sexual steroids.
DESIGN:

Pilot pharmacokinetics study.
SETTING:

Department of Obstetrics and Gynecology and Institute of Pharmacology, Medical Faculty, Palack? University, Olomouc; Department of Nuclear Medicine, University Hospital, Olomouc.
METHODS:

2 mg of estradiol valerate and 100 mg of micronized progesterone were given to eight healthy postmenopausal volunteers. Blood samples were collected at time 0, 2, 3, 5 and 24 hours after tablets application. The same trial was repeated a week later but tablets were swallowed with 200 ml of grapefruit juice. Serum levels of estradiol and progesterone were measured by RIA. Results were statistically evaluated using the Wilcoxon's nonparametric paired test.
RESULTS:

Though grapefruit juice on average slightly increased serum levels of estradiol (E2) and progesterone, this increase reached statistical significance only for the E2 level 24 hours after application of tablets. The mean area under curve (AUC) of estradiol rose significantly to 117%. The even greater increase in the mean AUC of progesterone (to 125%) was not statistically significant because of marked individual variability of response.
CONCLUSIONS:

Our results suggest that grapefruit juice may increase bioavailability of orally administered estradiol and progesterone. The response varies markedly between individuals. This observation may be of some importance also for users of OC and HRT.


PMID: 12749182 [PubMed - indexed for MEDLINE]



__________________________________________________ ____________________________________________

Article-

James Maskalyk
Editorial Fellow, CMAJ

Grapefruit juice interacts with a number of medications. This unusual discovery was made serendipitously in 1989 during an experiment designed to test the effect of ethanol on a calcium-channel blocker.1 The observed response was later determined to be due to the grapefruit juice delivery vehicle rather than the alcohol. In the past decade, the list of drug interactions with grapefruit juice has expanded to include several classes of medication, precipitating a recent advisory from Health Canada.2

The interaction: As little as 250 mL of grapefruit juice can change the metabolism of some drugs.3 This drug?food interaction occurs because of a common pathway involving a specific isoform of cytochrome P450 ? CYP3A4 ? present in both the liver and the intestinal wall. Studies suggest that grapefruit juice exerts its effect primarily at the level of the intestine.4

After ingestion, a substrate contained in the grapefruit binds to the intestinal isoenzyme, impairing first-pass metabolism directly and causing a sustained decrease in CYP3A4 protein expression.5 Within 4 hours of ingestion, a reduction in the effective CYP3A4 concentration occurs, with effects lasting up to 24 hours.6 The net result is inhibition of drug metabolism in the intestine and increased oral bioavailability. Because of the prolonged response, separating the intake of the drug and the juice does not prevent interference.

Individuals express CYP3A4 in different proportions, those with the highest intestinal concentration being most susceptible to grapefruit juice?drug interactions.5 An effect is seen with the whole fruit as well as its juice, so caution should be exercised with both.7 The precise chemical compound in grapefruit that causes the interaction has not been identified. There is no similar reaction with orange juice, although there is some suspicion that "sour oranges" such as the Seville variety, may have some effect.8 A recent study, however, that tested the known interference of grapefruit juice with cyclosporine showed no similar effect with Seville oranges.9

There is some interest in the potential therapeutic benefit of adding grapefruit juice to a drug regimen to increase oral bioavailability.3 The limitation is the individual variation in patient response. However, if the chemical that causes grapefruit's CYP3A4 inhibition is elucidated, there may be an opportunity to modulate that pathway in a controlled fashion.

What to do: Much of the data obtained on grapefruit juice?drug interactions involved measuring serum drug concentrations in small numbers of healthy volunteers. Because of the limited data and only occasional case reports,10 it is difficult to quantify the clinical significance for individual patients. One may assume that the interaction occurs primarily with oral medicines, and only with those that share the CYP3A4 metabolism pathway, with the consequence being increased oral bioavailability, higher serum drug concentrations and associated adverse effects.

Physicians should review medication lists often, with the goal of warning patients about adverse interactions. A list of medicines with which patients should not consume grapefruit is provided in Table 1.3,11,12 In the case of several medications that share the CYP3A4 metabolism pathway, but for which a clinical effect has not been elucidated or is theoretical, patients should be advised to consume grapefruit cautiously and be monitored for toxicity..

__________________________________________________ ______________________

Grapefruit juice?drug interactions

The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6′,7′-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.

Introduction

The opportunity for a food-drug interaction is an everyday occurrence. The interaction can be particularly important when total drug absorption is altered. Recently, a chance observation led to the finding that grapefruit juice can markedly increase the oral bioavailability of a number of medications [1]. This article retraces discovery of this novel interaction and reviews the mechanism of action, summaries both studied and predicted medications for an interaction, discusses possible active ingredient(s) in the juice and considers clinical implications


Discovery

Originally, a study was designed to test for an interaction between ethanol and the dihydropyridine calcium channel antagonist, felodipine [2], an analogue of nifedipine. Grapefruit juice was chosen to mask the taste of the ethanol following an assessment of every juice in a home refrigerator one Saturday evening. White grapefruit juice, particularly double-strength juice (single dilution of frozen concentrate), was the most effective. The combination of a non-intoxicating dose of ethanol and felodipine resulted in lower standing blood pressure and a high frequency of orthostatic hypotension compared with felodipine alone in patients with untreated borderline hypertension [2]. Although plasma felodipine concentrations were not different between treatments, they were several-fold higher than observed in other pharmacokinetic investigations with the same dose of drug. A systematic examination for obvious possible causes, such as incorrect dose or drug assay problems, did not resolve this discrepancy and eventually resulted in a pilot project in a single volunteer to judge the role of the juice. Plasma felodipine concentrations were more than five-fold greater with grapefruit juice compared with water .

Figure 1
Plasma felodipine concentration-time profile from the pilot study in which the effect of grapefruit juice was evaluated in one of the authors (DGB). Felodipine 5 mg regular tablet was administered with 350 ml double-strength grapefruit juice .

Mechanism

Felodipine disposition and metabolism

Felodipine has been the most extensively studied probe for grapefruit juice?drug interactions. Normally, felodipine is completely absorbed from the gastrointestinal tract following oral administration [3]. However, it undergoes high presystemic (first-pass) metabolism resulting in low absolute bioavailability averaging 15% [3] but ranging from 4% to 36% among individuals [4]. Both the gut wall and the liver appear responsible for presystemic felodipine elimination.

Figure 2
Sequential presystemic felodipine metabolism by CYP3A4 in apical enterocytes of the small bowel (A) and the hepatocytes of the liver (B) in the absence and presence of grapefruit juice. The percent of unmetabolized felodipine is presented before and after ...


Felodipine has a single primary metabolite, dehydrofelodipine [6], generated by cytochrome P450 3A4 (CYP3A4; Figure 3) [7]. Dehydrofelodipine is inactive and oxidized by two secondary pathways. The major secondary metabolite, M3, is also produced by CYP3A4 [8]. Apical enterocytes of the small bowel and hepatocytes of the liver both contain CYP3A4 [9, 10]. The content of CYP3A4 in both tissues ranges at least 10-fold among individuals and appears to be regulated independently of the other [11].

Pathways of felodipine metabolism.


Grapefruit juice effects

The first report of this interaction revealed that grapefruit juice, but not orange juice, tripled mean plasma felodipine area under the curve (AUC) compared to water in borderline hypertensive patients [12]. Blood pressure reduction, heart rate increase and frequency of vasodilatation-related adverse events were also greater. Grapefruit juice markedly elevated plasma peak felodipine concentration (Cmax

) but did not alter systemic felodipine elimination half-life (t1/2

) [12]. Since grapefruit juice did not change intravenous felodipine pharmacokinetics [5], it indicates that the interaction with grapefruit juice resulted from inhibition of presystemic drug metabolism.
Grapefruit juice reduced dehydrofelodipine/felodipine AUC ratio and increased absolute dehydrofelodipine AUC [1, 12]. The decrease in the AUC ratio was compatible with inhibition of the primary metabolic pathway. The absolute increase in dehydrofelodipine AUC indicated that a subsequent metabolic pathway might also be inhibited and this was supported by measurements showing that the M3 metabolite AUC was reduced [8]. Thus, grapefruit juice appeared to inhibit CYP3A4, an important isozyme of cytochrome P450 since it oxidizes a broad range of drugs and xenobiotics [13], with predominant and perhaps exclusive action on presystemic drug elimination.
Recently, the effect of grapefruit juice on drug metabolizing enzymes of the small bowel and liver was reported in an in vivoinvestigation in humans [14]. Grapefruit juice consumption for 5 days caused a mean 62% reduction of small bowel enterocyte CYP3A4 and CYP3A5 protein content associated with a greater than 3- and 5-fold increase in felodipine AUC andCmax, respectively. In contrast, liver CYP3A4 activity, as measured by the erythromycin breath test, and colon CYP3A5 protein content were not altered. Also, intestinal CYP2D6 and CYP1A1 protein content were not affected. Although these changes were measured after 5 days of grapefruit juice, preliminary data also showed that small bowel CYP3A4 can be markedly reduced 4 h after a single glass of juice. Consequently, it was concluded that grapefruit juice acted by selectively inhibiting CYP3A isozymes of the small bowel to cause greater felodipine oral bioavailability.
Decreased expression of CYP3A isoforms by grapefruit juice implied that the interaction was not simple competition for substrate metabolism. Since small bowel CYP3A4 mRNA was not changed [14], grapefruit juice likely decreased CYP3A4 protein content by a post-transcriptional mechanism, possibly involving accelerated CYP3A4 degradation through mechanism-based enzyme inhibition. Thus, the return of CYP3A4 activity would require de novo enzyme synthesis which could result in prolonged effect of grapefruit juice.
The duration of activity of grapefruit juice has been studied. In one study, consumption of a single glass (200 ml) of juice at various time intervals before felodipine showed that the extent of increase in felodipine AUC and Cmax was maximal between simultaneous and 4 h previous juice administration with drug [15]. Then, the magnitude of the interaction declined slowly with increasing time interval between grapefruit juice and felodipine administration. The half-life of effect of grapefruit juice was estimated at 12 h. Higher felodipine Cmax was still evident when grapefruit juice was consumed 24 h before felodipine. In another investigation, the effect of routine grapefruit juice consumption was evaluated [14]. One glass (250 ml) of grapefruit juice augmented mean felodipine AUC and Cmax to 267% and 345%, respectively, of that compared with water. Grapefruit juice three times daily with meals for 5 days further increased felodipine AUC and Cmax to 345% and 538% of that compared with water showing a cumulative effect of the juice.
The magnitude of the interaction was highly variable among individuals ranging from no change to six-fold greater plasma felodipine AUC and Cmax with grapefruit juice compared with water under single dose conditions [1, 8, 14, 16]. However, it was reproducible within individuals following repeat testing and thus, dependent on factors inherent to the individual [16]. Grapefruit juice reduced small bowel CYP3A4 content contingent upon pretreatment levels [14]. Individuals with the highest small bowel CYP3A4 content before grapefruit juice had the largest reduction in CYP3A4 and highest increase in felodipineCmax with grapefruit juice. Consequently, individual disparity in the magnitude of interaction with grapefruit juice appears at least partially explained by innate differences in baseline small bowel CYP3A4 protein content.

- - - Updated - - -

Conclusions

A single glass of grapefruit juice has the potential to augment the oral bioavailability and to enhance the beneficial or adverse effects of a broad range of medications, even by juice consumed hours beforehand. Grapefruit juice acts by inhibiting presystemic drug metabolism mediated by CYP3A isoforms in the small bowel. The interaction appears particularly relevant for medications with at least a doubling of plasma drug concentration or with a steep concentration-response relationship or a narrow therapeutic index. Patients that appear particularly susceptible have high small bowel CYP3A4 content, hepatic insufficiency or a pre-existing medical condition which predisposes to enhanced, excessive or abnormal drug effects. Since grocers do not take a drug history, physicians, pharmacists and other health professionals should educate patients about consumption of grapefruit juice with medications.
Isolation of the active ingredient(s) may lead to identification of other foods producing this interaction or to its incorporation into pharmaceutical formulations. Further research is required to understand the interaction better during routine grapefruit juice consumption, at amounts considered safe for administration with drugs and with different patient populations. Nevertheless, the serendipitous observation of increased plasma felodipine concentrations by grapefruit juice has provided fundamental new knowledge to improve pharmacotherapy and to stimulate research.

 

[ant29]

Increase potency oral steroids ( grapefruit juice increase the bioavailability )

Visions addition to a cheap and cost effect method to help increase the potency and bioavailability of oral steroids.

For sometime now I've known about this practice,and heard amazing results from people utilizing this protocol, with exceptional results.. I to have used this method and seen/felt pronounced effects with the oral I was taking..With low dosages,warning though, this can lead to liver toxicity levels if abused!
This method is also commonly used in the manufacturing process of some pro-hormones, with grapefruit exact added to the binders/fillers!

Grapefruit extract or juice also has a this pronounced effect with medications and YES including steroids!

Grapefruit juice will increase the potency of most oral drugs including steroids here is the article and a blind study

Study-

Ceska Gynekol. 2003 Mar;68(2):117-21.
[Does grapefruit juice increase the bioavailability of orally administered sex steroids?].

[Article in Czech]
Fingerov? H, Oborn? I, Petrov? P, Bud?kov? M, Jezd?nsk? J.
Source

Klinika porodnictv? a gynekologie LF UP v Olomouci.

Abstract

OBJECTIVE:

To verify if and to which extent the interaction with grapefruit juice can increase bioavailability of orally administered sexual steroids.
DESIGN:

Pilot pharmacokinetics study.
SETTING:

Department of Obstetrics and Gynecology and Institute of Pharmacology, Medical Faculty, Palack? University, Olomouc; Department of Nuclear Medicine, University Hospital, Olomouc.
METHODS:

2 mg of estradiol valerate and 100 mg of micronized progesterone were given to eight healthy postmenopausal volunteers. Blood samples were collected at time 0, 2, 3, 5 and 24 hours after tablets application. The same trial was repeated a week later but tablets were swallowed with 200 ml of grapefruit juice. Serum levels of estradiol and progesterone were measured by RIA. Results were statistically evaluated using the Wilcoxon's nonparametric paired test.
RESULTS:

Though grapefruit juice on average slightly increased serum levels of estradiol (E2) and progesterone, this increase reached statistical significance only for the E2 level 24 hours after application of tablets. The mean area under curve (AUC) of estradiol rose significantly to 117%. The even greater increase in the mean AUC of progesterone (to 125%) was not statistically significant because of marked individual variability of response.
CONCLUSIONS:

Our results suggest that grapefruit juice may increase bioavailability of orally administered estradiol and progesterone. The response varies markedly between individuals. This observation may be of some importance also for users of OC and HRT.


PMID: 12749182 [PubMed - indexed for MEDLINE]



__________________________________________________ ____________________________________________

Article-

James Maskalyk
Editorial Fellow, CMAJ

Grapefruit juice interacts with a number of medications. This unusual discovery was made serendipitously in 1989 during an experiment designed to test the effect of ethanol on a calcium-channel blocker.1 The observed response was later determined to be due to the grapefruit juice delivery vehicle rather than the alcohol. In the past decade, the list of drug interactions with grapefruit juice has expanded to include several classes of medication, precipitating a recent advisory from Health Canada.2

The interaction: As little as 250 mL of grapefruit juice can change the metabolism of some drugs.3 This drug?food interaction occurs because of a common pathway involving a specific isoform of cytochrome P450 ? CYP3A4 ? present in both the liver and the intestinal wall. Studies suggest that grapefruit juice exerts its effect primarily at the level of the intestine.4

After ingestion, a substrate contained in the grapefruit binds to the intestinal isoenzyme, impairing first-pass metabolism directly and causing a sustained decrease in CYP3A4 protein expression.5 Within 4 hours of ingestion, a reduction in the effective CYP3A4 concentration occurs, with effects lasting up to 24 hours.6 The net result is inhibition of drug metabolism in the intestine and increased oral bioavailability. Because of the prolonged response, separating the intake of the drug and the juice does not prevent interference.

Individuals express CYP3A4 in different proportions, those with the highest intestinal concentration being most susceptible to grapefruit juice?drug interactions.5 An effect is seen with the whole fruit as well as its juice, so caution should be exercised with both.7 The precise chemical compound in grapefruit that causes the interaction has not been identified. There is no similar reaction with orange juice, although there is some suspicion that "sour oranges" such as the Seville variety, may have some effect.8 A recent study, however, that tested the known interference of grapefruit juice with cyclosporine showed no similar effect with Seville oranges.9

There is some interest in the potential therapeutic benefit of adding grapefruit juice to a drug regimen to increase oral bioavailability.3 The limitation is the individual variation in patient response. However, if the chemical that causes grapefruit's CYP3A4 inhibition is elucidated, there may be an opportunity to modulate that pathway in a controlled fashion.

What to do: Much of the data obtained on grapefruit juice?drug interactions involved measuring serum drug concentrations in small numbers of healthy volunteers. Because of the limited data and only occasional case reports,10 it is difficult to quantify the clinical significance for individual patients. One may assume that the interaction occurs primarily with oral medicines, and only with those that share the CYP3A4 metabolism pathway, with the consequence being increased oral bioavailability, higher serum drug concentrations and associated adverse effects.

Physicians should review medication lists often, with the goal of warning patients about adverse interactions. A list of medicines with which patients should not consume grapefruit is provided in Table 1.3,11,12 In the case of several medications that share the CYP3A4 metabolism pathway, but for which a clinical effect has not been elucidated or is theoretical, patients should be advised to consume grapefruit cautiously and be monitored for toxicity..

__________________________________________________ ______________________

Grapefruit juice?drug interactions

The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6′,7′-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.

Introduction

The opportunity for a food-drug interaction is an everyday occurrence. The interaction can be particularly important when total drug absorption is altered. Recently, a chance observation led to the finding that grapefruit juice can markedly increase the oral bioavailability of a number of medications [1]. This article retraces discovery of this novel interaction and reviews the mechanism of action, summaries both studied and predicted medications for an interaction, discusses possible active ingredient(s) in the juice and considers clinical implications


Discovery

Originally, a study was designed to test for an interaction between ethanol and the dihydropyridine calcium channel antagonist, felodipine [2], an analogue of nifedipine. Grapefruit juice was chosen to mask the taste of the ethanol following an assessment of every juice in a home refrigerator one Saturday evening. White grapefruit juice, particularly double-strength juice (single dilution of frozen concentrate), was the most effective. The combination of a non-intoxicating dose of ethanol and felodipine resulted in lower standing blood pressure and a high frequency of orthostatic hypotension compared with felodipine alone in patients with untreated borderline hypertension [2]. Although plasma felodipine concentrations were not different between treatments, they were several-fold higher than observed in other pharmacokinetic investigations with the same dose of drug. A systematic examination for obvious possible causes, such as incorrect dose or drug assay problems, did not resolve this discrepancy and eventually resulted in a pilot project in a single volunteer to judge the role of the juice. Plasma felodipine concentrations were more than five-fold greater with grapefruit juice compared with water .

Figure 1
Plasma felodipine concentration-time profile from the pilot study in which the effect of grapefruit juice was evaluated in one of the authors (DGB). Felodipine 5 mg regular tablet was administered with 350 ml double-strength grapefruit juice .

Mechanism

Felodipine disposition and metabolism

Felodipine has been the most extensively studied probe for grapefruit juice?drug interactions. Normally, felodipine is completely absorbed from the gastrointestinal tract following oral administration [3]. However, it undergoes high presystemic (first-pass) metabolism resulting in low absolute bioavailability averaging 15% [3] but ranging from 4% to 36% among individuals [4]. Both the gut wall and the liver appear responsible for presystemic felodipine elimination.

Figure 2
Sequential presystemic felodipine metabolism by CYP3A4 in apical enterocytes of the small bowel (A) and the hepatocytes of the liver (B) in the absence and presence of grapefruit juice. The percent of unmetabolized felodipine is presented before and after ...


Felodipine has a single primary metabolite, dehydrofelodipine [6], generated by cytochrome P450 3A4 (CYP3A4; Figure 3) [7]. Dehydrofelodipine is inactive and oxidized by two secondary pathways. The major secondary metabolite, M3, is also produced by CYP3A4 [8]. Apical enterocytes of the small bowel and hepatocytes of the liver both contain CYP3A4 [9, 10]. The content of CYP3A4 in both tissues ranges at least 10-fold among individuals and appears to be regulated independently of the other [11].

Pathways of felodipine metabolism.


Grapefruit juice effects

The first report of this interaction revealed that grapefruit juice, but not orange juice, tripled mean plasma felodipine area under the curve (AUC) compared to water in borderline hypertensive patients [12]. Blood pressure reduction, heart rate increase and frequency of vasodilatation-related adverse events were also greater. Grapefruit juice markedly elevated plasma peak felodipine concentration (Cmax

) but did not alter systemic felodipine elimination half-life (t1/2

) [12]. Since grapefruit juice did not change intravenous felodipine pharmacokinetics [5], it indicates that the interaction with grapefruit juice resulted from inhibition of presystemic drug metabolism.
Grapefruit juice reduced dehydrofelodipine/felodipine AUC ratio and increased absolute dehydrofelodipine AUC [1, 12]. The decrease in the AUC ratio was compatible with inhibition of the primary metabolic pathway. The absolute increase in dehydrofelodipine AUC indicated that a subsequent metabolic pathway might also be inhibited and this was supported by measurements showing that the M3 metabolite AUC was reduced [8]. Thus, grapefruit juice appeared to inhibit CYP3A4, an important isozyme of cytochrome P450 since it oxidizes a broad range of drugs and xenobiotics [13], with predominant and perhaps exclusive action on presystemic drug elimination.
Recently, the effect of grapefruit juice on drug metabolizing enzymes of the small bowel and liver was reported in an in vivoinvestigation in humans [14]. Grapefruit juice consumption for 5 days caused a mean 62% reduction of small bowel enterocyte CYP3A4 and CYP3A5 protein content associated with a greater than 3- and 5-fold increase in felodipine AUC andCmax, respectively. In contrast, liver CYP3A4 activity, as measured by the erythromycin breath test, and colon CYP3A5 protein content were not altered. Also, intestinal CYP2D6 and CYP1A1 protein content were not affected. Although these changes were measured after 5 days of grapefruit juice, preliminary data also showed that small bowel CYP3A4 can be markedly reduced 4 h after a single glass of juice. Consequently, it was concluded that grapefruit juice acted by selectively inhibiting CYP3A isozymes of the small bowel to cause greater felodipine oral bioavailability.
Decreased expression of CYP3A isoforms by grapefruit juice implied that the interaction was not simple competition for substrate metabolism. Since small bowel CYP3A4 mRNA was not changed [14], grapefruit juice likely decreased CYP3A4 protein content by a post-transcriptional mechanism, possibly involving accelerated CYP3A4 degradation through mechanism-based enzyme inhibition. Thus, the return of CYP3A4 activity would require de novo enzyme synthesis which could result in prolonged effect of grapefruit juice.
The duration of activity of grapefruit juice has been studied. In one study, consumption of a single glass (200 ml) of juice at various time intervals before felodipine showed that the extent of increase in felodipine AUC and Cmax was maximal between simultaneous and 4 h previous juice administration with drug [15]. Then, the magnitude of the interaction declined slowly with increasing time interval between grapefruit juice and felodipine administration. The half-life of effect of grapefruit juice was estimated at 12 h. Higher felodipine Cmax was still evident when grapefruit juice was consumed 24 h before felodipine. In another investigation, the effect of routine grapefruit juice consumption was evaluated [14]. One glass (250 ml) of grapefruit juice augmented mean felodipine AUC and Cmax to 267% and 345%, respectively, of that compared with water. Grapefruit juice three times daily with meals for 5 days further increased felodipine AUC and Cmax to 345% and 538% of that compared with water showing a cumulative effect of the juice.
The magnitude of the interaction was highly variable among individuals ranging from no change to six-fold greater plasma felodipine AUC and Cmax with grapefruit juice compared with water under single dose conditions [1, 8, 14, 16]. However, it was reproducible within individuals following repeat testing and thus, dependent on factors inherent to the individual [16]. Grapefruit juice reduced small bowel CYP3A4 content contingent upon pretreatment levels [14]. Individuals with the highest small bowel CYP3A4 content before grapefruit juice had the largest reduction in CYP3A4 and highest increase in felodipineCmax with grapefruit juice. Consequently, individual disparity in the magnitude of interaction with grapefruit juice appears at least partially explained by innate differences in baseline small bowel CYP3A4 protein content.

- - - Updated - - -

Conclusions

A single glass of grapefruit juice has the potential to augment the oral bioavailability and to enhance the beneficial or adverse effects of a broad range of medications, even by juice consumed hours beforehand. Grapefruit juice acts by inhibiting presystemic drug metabolism mediated by CYP3A isoforms in the small bowel. The interaction appears particularly relevant for medications with at least a doubling of plasma drug concentration or with a steep concentration-response relationship or a narrow therapeutic index. Patients that appear particularly susceptible have high small bowel CYP3A4 content, hepatic insufficiency or a pre-existing medical condition which predisposes to enhanced, excessive or abnormal drug effects. Since grocers do not take a drug history, physicians, pharmacists and other health professionals should educate patients about consumption of grapefruit juice with medications.
Isolation of the active ingredient(s) may lead to identification of other foods producing this interaction or to its incorporation into pharmaceutical formulations. Further research is required to understand the interaction better during routine grapefruit juice consumption, at amounts considered safe for administration with drugs and with different patient populations. Nevertheless, the serendipitous observation of increased plasma felodipine concentrations by grapefruit juice has provided fundamental new knowledge to improve pharmacotherapy and to stimulate research.

Vision is always on point with his responses.... I always look forward to what he has to say. He also always has a study to back his info . He is a book of great knowledge .


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[Brendanj9554]

That's for the info guys. I am most likely a non responder. I have tried many different labs for oral. Hence why I have ordered raw to see if liquid oral will be any better. And I will give the grapefruit a try when my raws arrive. Like I said in another thread. EP are good to go and have had excellent results with injectables. Many of my friends hav run Orals with great results, me however.... Different story

 

[JRotten]

Yep DJ gave me a green light on the halo. Just thought I'd start the conversation

 

[Brendanj9554]

Ok guys. My apologies..... It seems that I was using a different EP to the products pictured. I am from the UK and my domestic source supply's EP (euro pharma) and it's not the same as pictured.

I I will add a picture of the product I thought the OP was talking about. Please ignore my opinion as it seems it's a totally different source.

Moon the other hand I may be a non responder. As I said in my post, I have no luck with Orals. And that's from any lab.

Sorry guys

http://forums.steroid.com/attachmen...harma-first-cycle-age-17-image-4279783731.jpg

 

[spinyvegeta]

I've ran the dbol. Hit me so quick, had to up my AI because my nipples had puffed up. Strength is excellent

 

[Vision]

Ok guys. My apologies..... It seems that I was using a different EP to the products pictured. I am from the UK and my domestic source supply's EP (euro pharma) and it's not the same as pictured.

I I will add a picture of the product I thought the OP was talking about. Please ignore my opinion as it seems it's a totally different source.

Moon the other hand I may be a non responder. As I said in my post, I have no luck with Orals. And that's from any lab.

Sorry guys

http://forums.steroid.com/attachmen...harma-first-cycle-age-17-image-4279783731.jpg

No where is my brother, it's very easy to get labs confused especially in the geographical location that they are because many other labs have similar names..

With my suggestion, definitely come back and let us know how you make out because I think that would be a complete game changer with your experience... it's a shame that you did not gain any good results, but that's not the end of the game for you brother there's other options available... definitely let us know how you make out my man...

I've ran the dbol. Hit me so quick, had to up my AI because my nipples had puffed up. Strength is excellent

This is actually huge, because I'm going to take into great consideration everything you said because I am very sensitive.... as a precaution I may even begin my anti in advance

 

[spinyvegeta]

I would do that Vision. Strongest stuff I ran so far

 

[Vision]

I've ran the dbol. Hit me so quick, had to up my AI because my nipples had puffed up. Strength is excellent

I would do that Vision. Strongest stuff I ran so far

You have no idea how excited I am right now, I respond so well to this compound I'm truly super excited... thank you for your feedback brother

 

[ldog]

V,

Why not run the Ldog speacial and use 10mg pre workout till you get a good idea how your going to respond? Poor old lion.....things just aren't like they used to be...

 

[Vision]

Ok guys. My apologies..... It seems that I was using a different EP to the products pictured. I am from the UK and my domestic source supply's EP (euro pharma) and it's not the same as pictured.

I I will add a picture of the product I thought the OP was talking about. Please ignore my opinion as it seems it's a totally different source.

Moon the other hand I may be a non responder. As I said in my post, I have no luck with Orals. And that's from any lab.

Sorry guys

http://forums.steroid.com/attachmen...harma-first-cycle-age-17-image-4279783731.jpg

I've ran the dbol. Hit me so quick, had to up my AI because my nipples had puffed up. Strength is excellent

V,

Why not run the Ldog speacial and use 10mg pre workout till you get a good idea how your going to respond? Poor old lion.....things just aren't like they used to be...

A matter fact I think your suggestion would be more ideal to my instance... low dose actually does pretty well with me because like I said I respond very very well, at times too well for my own i.e. BLOAT!

I can always add, subtracting can be a bitch because of unwanted

 

[JRotten]

I like the dbol 10mg dosage. Quality dbol is probably the most versatile oral steroid out there but you have to be able to adjust the dose reliably. Good halo is great as a pre at 20, but again being able to choose a dosing strategy is very useful for such quick acting compounds. Having said that, it also exposes the lab a bit when you can really test these products at low doses. If it's not right you'll know quickly. It's a gamble.

 

[ldog]

Good points bro.^^^^^

 

[jozifp103]

​Coincidentally I just started the dbol today. Decided to try a mid-cycle dbol run instead of a kick starter. I feel The results may be more permanent with my test/deca levels peaked. instead of running dbol as a kicker with the levels not built up yet. I have no science to back this up, but I'm a firm believer in experience trumps studies. Popped 20mg this morning and popping another 30mg pre WO. Pretty excited to say the least. I like quick gains, and I love the euphoria that dbol gives me. It's a happy pill for me.

 

[Vision]

​Coincidentally I just started the dbol today. Decided to try a mid-cycle dbol run instead of a kick starter. I feel The results may be more permanent with my test/deca levels peaked. instead of running dbol as a kicker with the levels not built up yet. I have no science to back this up, but I'm a firm believer in experience trumps studies. Popped 20mg this morning and popping another 30mg pre WO. Pretty excited to say the least. I like quick gains, and I love the euphoria that dbol gives me. It's a happy pill for me.

Listen, your on to something and its actually been tested, tried and proven true.. Due to the synergistic effects with the relations of all compounds working by more than one specific mechanism,
your entirely activating the AR's from inside out, at the same time improving CNS and muscle connection,growth from AAS doesn't necessarily have to be AR mediators, with the combination of non and actually AR mediators improve satellite cells (improve cellular chatter) neuro activation/activity, and protein/nitrogen synthesis and nutrient expression is in sync complimenting one an other..

This is why I either kick start with drol or dbol, but add one of the either mid way, at times low dose combo. So, there is actually science behind this!

Kudos to you for mentioning this!

 

[frank zazz]

It was a while back but I'm pretty sure Bronson ran their halo I need to find the old thread he loved it.

It was ep halo

 

[ldog]

Guys...I can run Dbol at a low dose for months.....and I mean months....8 months at one point. The wellness feeling is one of the key reasons I like to stay on most of the time. Unlike other compounds, I never seem to build up a tolerance. I usually switch up from morning dose for a few months to pre workout for a few months to right before bed for a time.

 

[galois]

Guys...I can run Dbol at a low dose for months.....and I mean months....8 months at one point. The wellness feeling is one of the key reasons I like to stay on most of the time. Unlike other compounds, I never seem to build up a tolerance. I usually switch up from morning dose for a few months to pre workout for a few months to right before bed for a time.

What do you mean by a low dose? How does your liver like that?

 

[ldog]

10mg

My liver enzymes are barely if any out of range..AST and ALT.....GGT stays well within range.

 

[sneedam]

10mg

My liver enzymes are barely if any out of range..AST and ALT.....GGT stays well within range.

Idog or V,
I am not a big lover of orals, but that is because when I tried British dragon D-bol along with test it made me feel like shit. I stuck with it just long enough to feel some strength gains coming hard and fast. I do not understand why I felt like shit, lethargy galore and I never went over 20mg, dosing 10mg twice a day? WTH? I still have some left but will not touch it.....Was it a bad batch or do some people just react so harshly????? I have never been able to get a straight answer to this. I was forced into thinking it was bunk or maybe mixed with var but that would not make sense from a profit stand point.....I don't know.......

 

[Vision]

Idog or V,
I am not a big lover of orals, but that is because when I tried British dragon D-bol along with test it made me feel like shit. I stuck with it just long enough to feel some strength gains coming hard and fast. I do not understand why I felt like shit, lethargy galore and I never went over 20mg, dosing 10mg twice a day? WTH? I still have some left but will not touch it.....Was it a bad batch or do some people just react so harshly????? I have never been able to get a straight answer to this. I was forced into thinking it was bunk or maybe mixed with var but that would not make sense from a profit stand point.....I don't know.......

That could be a variety of things, from the reaction within your gastro track ( a lot of oral medications will possess this problem in some users due to the presence of enzymes, especially with multi vitamins that are hard-pressed) or you could be having a slight response to the binders and fillers ( specifically the cellulose ) within the oral Dianabol... believe it or not nausea is not uncommon, or the feeling of lethargic.... it could be a shift with metabolising yielding a greater presence of estrogen ( this could be a reason for feeling lethargic ).... I would suggest consuming with food to help eliminate any gastro disturbance or possibly feeling lethargic after taking, definitely taking an AI will also be recommended...

Some guys switch to Anadrol and do not have this problem, and vice versa...

I would try a different brand because they may possess different binders and fillers, and dies... but definitely take with an anti estrogen and food.. Process of elimination

 

[Dieseljimmy]

Halo and adex feel beuno.

I used to get ep tbol all the time. It's the most underated oral around.

I'm going to obtain some ep methyltest and maybe some cialis in the foresee able future

 

[Vision]

Halo and adex feel beuno.

I used to get ep tbol all the time. It's the most underated oral around.

I'm going to obtain some ep methyltest and maybe some cialis in the foresee able future

Awesome news on the adex, Im starting it tomm, as I just started my blast with the orals.. we shall see..

 

[sneedam]

Thanks vision, I will give it another try after a bit, I would love to feel this euphoric feeling everyone seems to get.

 

[ldog]

Sneedam,

Thanks for the question.

I can say with certainty that the brand of Dbol can make a world of difference. As you know, our quality is well known so it's worth a try for you to give EP Dbol a go. Start with a low dose and get a feel for the product. Quality Dbol doesn't require a high dose for proven results. With that said, some folks just plain react badly to orals but before you can firmly say that this is you, try the EP product. Aside from Dbol, I would recommend some Tbol from EP. This could be a good fit for you. Please keep me posted on your progress.

Thanks for for your loyalty.