(Refresher for those just joining Ology)
Increase potency of oral steroids ( grapefruit juice increase the bioavailability )
Visions addition to a cheap and cost effective method to help increase the potency and bioavailability of oral steroids. ( grapefruit juice increase the bioavailability )
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 vitrofindings support the flavonoid, naringin, or the furanocoumarin, 6***8242;,7***8242;-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].
Increase potency of oral steroids ( grapefruit juice increase the bioavailability )
Visions addition to a cheap and cost effective method to help increase the potency and bioavailability of oral steroids. ( grapefruit juice increase the bioavailability )
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 vitrofindings support the flavonoid, naringin, or the furanocoumarin, 6***8242;,7***8242;-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 ********* pathway. The absolute increase in dehydrofelodipine AUC indicated that a subsequent ********* 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.
Kind regards,
Vision
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 ********* pathway. The absolute increase in dehydrofelodipine AUC indicated that a subsequent ********* 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.
Kind regards,
Vision
