Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: Consequences for FK506 assimilation

Lemahieu, Wim; Maes, Bart; Verbeke, Kristin; Vanrenterghem, Yves

doi:10.1111/j.1523-1755.2005.00182.x

Cited by 18 publications

(10 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The strongest effects on calcineurininhibitor disposition are observed with azole antifungals, macrolide antibacterials, rifampicin, calcium channel antagonists, grapefruit juice, St John Wort and protease inhibitors. As for omeprazole, which was inconsistently found to have a pharmacokinetic interaction with tacrolimus, 41 there was no significant association here. The frequency of drug-drug interactions is high in most solid organ transplant recipients because of polypharmacy.…”

Section: Discussioncontrasting

confidence: 59%

The Impact of Sulfonylureas on Tacrolimus Apparent Clearance Revealed by a Population Pharmacokinetics Analysis in Chinese Adult Liver-Transplant Patients

Zhang¹,

Wang²,

Fan³

et al. 2012

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

show abstract

Section: Discussioncontrasting

confidence: 59%

The Impact of Sulfonylureas on Tacrolimus Apparent Clearance Revealed by a Population Pharmacokinetics Analysis in Chinese Adult Liver-Transplant Patients

Zhang¹,

Wang²,

Fan³

et al. 2012

Therapeutic Drug Monitoring

View full text Add to dashboard Cite

show abstract

“…This resulted in a more than four‐fold increase of the parent/metabolite ratio for M8 (Figure 3). The effect of omeprazole on CYP3A4 has been shown to be either conflicting or demonstrating an induction [4, 22], which would ultimately result in a decrease of plasma concentrations of the parent compound and an increase of the metabolites, with a decrease of the metabolic ratio. Our findings therefore suggest a role of CYP2C19 in the metabolism of etravirine due to inhibition by omeprazole, affecting metabolite M8, rather than an effect on CYP3A4.…”

Section: Discussionmentioning

confidence: 99%

“…No major interaction of omeprazole with the CYP3A4 substrate ciclosporin was described previously [20]. In another study, a 40% reduction of the metabolite excretion of the CYP3A probe dapsone was shown, although a study in renal transplant patients has demonstrated a decrease of tacrolimus exposure when co‐administered with omeprazole, attributed to the induction of intestinal CYP3A4 activity [21, 22].…”

Section: Introductionmentioning

confidence: 97%

A pharmacokinetic study of etravirine (TMC125) co‐administered with ranitidine and omeprazole in HIV–negative volunteers

Schöller-Gyüre¹,

Kakuda²,

Smedt³

et al. 2008

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Drug-drug interactions with acid-suppressing agents were previously described with several other antiretroviral drugs.• Etravirine (TMC125) is a next-generation non-nucleoside reverse transcriptase inhibitor, metabolized by CYP3A and CYP2C enzymes with demonstrated efficacy in treatment-experienced HIV-infected patients.• The effect of acid-suppressing agents on the pharmacokinetics of etravirine was unknown. WHAT THIS STUDY ADDS• No clinically relevant effect was shown on the pharmacokinetics of etravirine when co-administered with ranitidine or omeprazole, drugs that increase gastric pH.• A drug-drug interaction due to CYP2C19 inhibition by omeprazole has been identified.• Etravirine can be co-administered with proton pump inhibitors and H2 antagonists without dose adjustments. AimsEtravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H2-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine. MethodsIn an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out. ResultsNineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUClast and Cmax were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated. ConclusionsRanitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H2 antagonists without dose adjustments.

show abstract

“…To avoid this complication, we tested our hypothesis in a proofof-concept study using both cimetidine and ranitidine. Although cimetidine is a strong inhibitor of P450 enzymes in both humans and animals, ranitidine is considered a weak inhibitor with an affinity for P450 that is 10 times lower than that of cimetidine [21][22][23]. Therefore, any differences between cimetidine and ranitidine in their effects on IR injury would be due, most likely, to P450 inhibition by cimetidine.…”

Section: Introductionmentioning

confidence: 98%

Effects of Cytochrome P450 Inhibition by Cimetidine on the Warm Hepatic Ischemia-Reperfusion Injury in Rats

Shaik

Mehvar

2010

Journal of Surgical Research

View full text Add to dashboard Cite

Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: Consequences for FK506 assimilation

Abstract: Switching treatment with cimetidine to omeprazole in renal transplant recipients is associated with a decrease of dose/weight normalized trough levels of tacrolimus. Studies in healthy volunteers suggest that this may be explained by an increase of intestinal CYP3A4 activity.

Cited by 18 publications

References 29 publications

The Impact of Sulfonylureas on Tacrolimus Apparent Clearance Revealed by a Population Pharmacokinetics Analysis in Chinese Adult Liver-Transplant Patients

The Impact of Sulfonylureas on Tacrolimus Apparent Clearance Revealed by a Population Pharmacokinetics Analysis in Chinese Adult Liver-Transplant Patients

A pharmacokinetic study of etravirine (TMC125) co‐administered with ranitidine and omeprazole in HIV–negative volunteers

Effects of Cytochrome P450 Inhibition by Cimetidine on the Warm Hepatic Ischemia-Reperfusion Injury in Rats

Contact Info

Product

Resources

About