Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity <i>in vivo</i> without altering the expression of intestinal mRNA or protein

Pinto, Amar G.; Horlander, John C.; Chalasani, Naga; Hamman, Mitchell A.; Asghar, Ali; Kolwankar, Dhanashri; Hall, Stephen D.

doi:10.1111/j.1365-2125.2005.02343.x

Cited by 29 publications

(26 citation statements)

References 25 publications

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“…In contrast to assuming F G Ј ϭ 1, the assumption that diltiazem reduces intestinal CYP3A4 activity by 62% (assessed by midazolam 1Ј-hydroxylation; Pinto et al, 2005) reduced this ratio and the extent of overpredictions, mainly for cyclosporine and buspirone interactions, respectively, by 54 to 190%; however, the predictions were still outside the 2-fold limits of in vivo values, in particular, for cyclosporine.…”

Section: Galetin Et Almentioning

confidence: 68%

Prediction of Time-Dependent Cyp3a4 Drug-Drug Interactions: Impact of Enzyme Degradation, Parallel Elimination Pathways, and Intestinal Inhibition

Galetin¹,

Burt²,

Gibbons³

et al. 2005

Drug Metab Dispos

153

133

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ABSTRACT:Time-dependent inhibition of CYP3A4 often results in clinically significant drug-drug interactions. In the current study, 37 in vivo cases of irreversible inhibition were collated, focusing on macrolides (erythromycin, clarithromycin, and azithromycin) and diltiazem as inhibitors. The interactions included 17 different CYP3A substrates showing up to a 7-fold increase in AUC (13.5% of studies were in the range of potent inhibition). A systematic analysis of the impact of CYP3A4 degradation half-life (mean t 1/2deg ‫؍‬ 3 days, ranging from 1 to 6 days) on the prediction of the extent of interaction for compounds with a differential contribution from CYP3A4 to the overall elimination (defined by fm CYP3A4 ) was performed. Although the prediction accuracy was very sensitive to the CYP3A4 degradation rate for substrates mainly eliminated by this enzyme (fm CYP3A4 > 0.9), minimal effects are observed when CYP3A4 contributes less than 50% to the overall elimination in cases when the parallel elimination pathway is not subject to inhibition. Use of the mean CYP3A4 t 1/2deg (3 days), average unbound systemic plasma concentration of the inhibitor, and the corresponding fm CYP3A4 resulted in 89% of studies predicted within 2-fold of the in vivo value. The impact of the interaction in the gut wall was assessed by assuming maximal intestinal inhibition of CYP3A4. Although a reduced number of false-negative predictions was observed, there was an increased number of overpredictions, and generally, a loss of prediction accuracy was observed. The impact of the possible interplay between CYP3A4 and efflux transporters on the intestinal interaction requires further evaluation.As the most abundant human cytochrome P450 enzyme in both liver and intestine, CYP3A4 is susceptible to a number of reversible and irreversible metabolic drug-drug interactions. Irreversible, often referred to as mechanism-based, inhibition interactions involve the metabolism of an inhibitor by CYP3A4 to a reactive metabolite which inactivates the catalyzing enzyme in a concentration-and time-dependent manner (Silverman, 1995). A key characteristic of this type of inhibition is that inactivation occurs without the release of the reaction product from the catalytic site (Kent et al., 2001). The interaction between the inactivating species and enzyme can either be covalent or noncovalent, involving binding to protein or heme moiety, respectively (Zhou et al., 2005).The two major kinetic parameters that characterize time-dependent inhibition interactions (TDIs) are k inact and K i , the maximal inactivation rate constant and the inhibitor concentration leading to 50% of k inact , respectively (Silverman, 1995). The k inact /K I ratio is commonly taken as an indicator of the in vitro potency of a mechanism-based inhibitor. The methods used to obtain k inact and K I estimates generally vary across studies: the CYP3A4 probes used (midazolam, testosterone, or triazolam), their concentration (from below the K m to the concentrations equivalent to V max ), pr...

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Section: Galetin Et Almentioning

confidence: 68%

Prediction of Time-Dependent Cyp3a4 Drug-Drug Interactions: Impact of Enzyme Degradation, Parallel Elimination Pathways, and Intestinal Inhibition

Galetin¹,

Burt²,

Gibbons³

et al. 2005

Drug Metab Dispos

153

133

View full text Add to dashboard Cite

show abstract

“…Closed circles in A are observed DTZ concentrations on day 1 and day 6 of DTZ treatment (Lefebvre et al, 1994). Closed circle with error bar in B is observed CYP3A4 activity on the morning of the 8th day (Pinto et al, 2005). metabolites that would otherwise be difficult to identify. With the additive model incorporated into the semi-PBPK model for the simultaneous inactivation by DTZ and nd-DTZ, the -fold increase of MDZ AUC after oral and intravenous administration was accurately predicted.…”

Section: Discussionmentioning

confidence: 99%

“…Therapeutically important interactions between oral diltiazem and midazolam (MDZ) (Backman et al, 1994), triazolam (Varhe et al, 1996), cyclosporine (Wagner et al, 1988), lovastatin (Azie et al, 1998;Masica et al, 2000), and carbamazepine (Brodie and MacPhee, 1986;Eimer and Carter, 1987) have been documented. A previous study by our group also demonstrated that DTZ (120 mg twice daily for 7 days) caused a 62% decrease in small bowel CYP3A4 activity (Pinto et al, 2005). Thus, irreversible inhibition of CYP3A by DTZ is the most likely explanation for the nonlinear pharmacokinetics of DTZ.…”

mentioning

confidence: 92%

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Semiphysiologically Based Pharmacokinetic Models for the Inhibition of Midazolam Clearance by Diltiazem and Its Major Metabolite

Zhang¹,

Quinney²,

Gorski³

et al. 2009

Drug Metab Dispos

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“…On the basis of in vitro models, clarithromycin was predicted to cause a reduction in the steady-state concentration of liver CYP3A4 to approximately 39% of the initial level (21). The mechanism of this autoinhibition was reported to be reversible (16,26), irreversible (2,15,25), and mediated by suicide inhibition by the formation of a metabolic intermediate complex (21). For clarithromycin, the ratio of the area under the free plasma concentration-time curve (fAUC) to the MIC is considered to be the most predictive pharmacokinetic-pharmacodynamic index (9,32) and is used to link the pharmacokinetic parameters to the most important antimicrobial pharmacodynamic parameter, i.e., the MIC.…”

mentioning

confidence: 99%

Modeling the Autoinhibition of Clarithromycin Metabolism during Repeated Oral Administration

Abduljalil

Kinzig

Bulitta

et al. 2009

Antimicrob Agents Chemother

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Diltiazem inhibits human intestinal cytochrome P450 3A (CYP3A) activity in vivo without altering the expression of intestinal mRNA or protein

Cited by 29 publications

References 25 publications

Prediction of Time-Dependent Cyp3a4 Drug-Drug Interactions: Impact of Enzyme Degradation, Parallel Elimination Pathways, and Intestinal Inhibition

Prediction of Time-Dependent Cyp3a4 Drug-Drug Interactions: Impact of Enzyme Degradation, Parallel Elimination Pathways, and Intestinal Inhibition

Semiphysiologically Based Pharmacokinetic Models for the Inhibition of Midazolam Clearance by Diltiazem and Its Major Metabolite

Modeling the Autoinhibition of Clarithromycin Metabolism during Repeated Oral Administration

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