Prediction of Cytochrome P450 3a Inhibition by Verapamil Enantiomers and Their Metabolites

Wang, Ying Hong; Jones, David R.; Hall, Stephen D.

doi:10.1124/dmd.32.2.259

Cited by 192 publications

(199 citation statements)

References 30 publications

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“…Diltiazem and verapamil were recently identified as inhibitors of human CES1 and CES2 (Yanjiao et al, 2013). In addition, both drugs are known inhibitors of CYP3A4 (Sutton et al, 1997;Wang et al, 2004). Thus, the inhibition of CES1 and CES2 provides an additional mechanism for drug-drug interactions caused by diltiazem and verapamil, and it widens the range of potentially affected drugs.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

2013

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Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensinconverting enzyme inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1-and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.

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Section: Discussionmentioning

confidence: 99%

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

2013

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“…This finding may be attributed to several factors. For example, although metabolites of several inhibitors are potent CYP3A inhibitors (Mayhew et al, 2000;Wang et al, 2004b;Zhao et al, 2007), the parent compounds have to be metabolized first to inactivate the enzyme; therefore, it is difficult to distinguish whether the parent compounds or their metabolites are responsible for CYP3A inactivation. In addition, for most inhibitors used in this study, the effect of autoinhibition may not be significant at the doses studied and could sometimes be dealt with by applying a large coefficient of variation of dmd.aspetjournals.org the clearance parameter (e.g., ritonavir).…”

Section: Summary Of Drug Interaction Predictions Using Inactivation Pmentioning

confidence: 99%

“…The static mathematical model developed by Mayhew et al (2000) is a commonly used approach to predict mechanism-based drug interactions from in vitro estimated inactivation parameters. Several modifications to the original model have been made to incorporate the effects of intestinal wall metabolism (Wang et al, 2004b), competitive inhibition, and induction (Fahmi et al, 2009). Nonetheless, these static models are only capable of predicting the average magnitude of drug interactions across a population, assuming that the steady state of enzyme inhibition has been reached.…”

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confidence: 99%

Confidence Assessment of the Simcyp Time-Based Approach and a Static Mathematical Model in Predicting Clinical Drug-Drug Interactions for Mechanism-Based CYP3A Inhibitors

Wang¹

2010

Drug Metab Dispos

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ABSTRACT:Accurate prediction of the extent of mechanism-based CYP3A inhibition is critical in determining the timing of clinical drug interaction studies in drug development. To evaluate the prediction accuracy of the static and Simcyp time-based approaches, 54 clinical drug interactions involving mechanism-based CYP3A inhibitors were predicted using both methods. The Simcyp timebased approach generated better prediction when 0.03 h ؊1 was used as the hepatic CYP3A enzyme degradation rate constant (k deg ) value. Of the predictions 87 and 55% had an error less than 2 and 0. Drug-drug interactions remain an area of focus in drug discovery and development. Mechanism-based inhibition of CYP3A is one of the major causes of clinical drug-drug interactions and generally leads to greater concern, as highlighted by the list of moderate and strong CYP3A inhibitors in the Food and Drug Administration (2006) Drug Interaction Guidance. The inhibitory effects of a mechanism-based CYP3A inhibitor persist long after the compound is eliminated from the body because the recovery of CYP3A enzyme activity requires de novo protein synthesis or slow release of the enzyme from the enzyme-inhibitor complex. Because of the primary role of CYP3A in drug disposition, prediction of the clinical drug interaction potential of a mechanism-based CYP3A inhibitor would be helpful in guiding the timing and design of clinical studies.Several approaches have been developed to predict clinical outcomes of mechanism-based inhibition. The static mathematical model developed by Mayhew et al. (2000) is a commonly used approach to predict mechanism-based drug interactions from in vitro estimated inactivation parameters. Several modifications to the original model have been made to incorporate the effects of intestinal wall metabolism (Wang et al., 2004b), competitive inhibition, and induction (Fahmi et al., 2009). Nonetheless, these static models are only capable of predicting the average magnitude of drug interactions across a population, assuming that the steady state of enzyme inhibition has been reached. Temporal changes in inhibitor concentrations and CYP3A enzyme activities as well as interindividual variability in CYP3A enzyme levels and rate constants of enzyme degradation are not considered. In addition, it is difficult to assess the effects of dosing regimens (e.g., irregular dosing) on the extent of drug interactions using a static model.Several physiologically based pharmacokinetic models (PBPK) were developed to address some of the aforementioned limitations with static models (Kanamitsu et al., 2000;Zhang et al., 2009;Fenneteau et al., 2010). These PBPK models take into account temporal changes in inhibitor and substrate concentrations and enzyme activities as well as the enzyme inhibition concept in the static models. They can be used to simulate drug concentrationtime profiles and to explore the effects of various dosing regimens. Simcyp (Simcyp Limited, Sheffield, UK) is a commercially available absorption, distribution, metabolism, and...

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“…However, although prediction bias was affected by the choice of microsomal pools, it had only a marginal effect on the precision of clearance predictions. The current analysis included three known inhibitors of CYP3A, namely indinavir, saquinavir, and verapamil (Eagling et al, 1997;Wang et al, 2004;Ernest et al, 2005). To avoid biased clearance estimates, incubations were performed at a substrate concentration below K i (for competitive inhibitors) or K I (time-dependent inhibitors) and over a short (Յ30 min) time period.…”

Section: Prediction Of Human Intestinal First-pass Metabolismmentioning

confidence: 99%

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

Gertz

Harrison²,

Houston³

et al. 2010

Drug Metab Dispos

270

233

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ABSTRACT:Intestinal first-pass metabolism may contribute to low oral drug bioavailability and drug-drug interactions, particularly for CYP3A substrates. The current analysis predicted intestinal availability (F G ) from in vitro metabolic clearance and permeability data of 25 drugs using the Q Gut model. The drug selection included a wide range of physicochemical properties and in vivo F G values (0.07-0.94). In vitro clearance data (CLu int ) were determined in human intestinal (HIM) and three liver (HLM) microsomal pools (n ‫؍‬ 105 donors) using the substrate depletion method. Apparent drug permeability (P app ) was determined in Caco-2 and Madin-Darby canine kidney cells transfected with human MDR1 gene (MDCK-MDR1 cells) under isotonic conditions (pH ‫؍‬ 7.4). In addition, effective permeability (P eff ) data, estimated from regression analyses to P app or physicochemical properties were used in the F G predictions. Determined CLu int values ranged from 0.022 to 76.7 l/min/pmol of CYP3A (zolpidem and nisoldipine, respectively). Differences in CLu int values obtained in HIM and HLM were not significant after normalization for tissue-specific CYP3A abundance, supporting their interchangeable usability. The F G predictions were most successful when P app data from Caco-2/MDCK-MDR1 cells were used directly; in contrast, the use of physicochemical parameters resulted in significant F G underpredictions. Good agreement between predicted and in vivo F G was noted for drugs with low to medium intestinal extraction (e.g., midazolam predicted F G value 0.54 and in vivo value 0.51). In contrast, low prediction accuracy was observed for drugs with in vivo F G <0.5, resulting in considerable underprediction in some instances, as for saquinavir (predicted F G is 6% of the observed value). Implications of the findings are discussed.

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Prediction of Cytochrome P450 3a Inhibition by Verapamil Enantiomers and Their Metabolites

Cited by 192 publications

References 30 publications

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

In Vitro Drug Metabolism by Human Carboxylesterase 1: Focus on Angiotensin-Converting Enzyme Inhibitors

Confidence Assessment of the Simcyp Time-Based Approach and a Static Mathematical Model in Predicting Clinical Drug-Drug Interactions for Mechanism-Based CYP3A Inhibitors

Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data

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