Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping

Lee, Jang-ik; Chaves‐Gnecco, Diego; Amico, Janet A.; Kroboth, Patricia D.; Wilson, John W.; Frye, Reginald F.

doi:10.1067/mcp.2002.129068

Cited by 85 publications

(76 citation statements)

References 27 publications

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“…Our results showed that two weeks ingestion of tenryocha and rooibos tea caused significant declines in AUC and C max of MDZ while there was no change in the elimination half life (Table 1). MDZ is a short-acting benzodiazepine derivative that is metabolized to 1'-hydroxymidazolam and 4-hydroxymidazolam mainly by CYP3A4 in humans and by CYP3A2 in rats, and it has been recognized as a sensitive prove to investigate CYP3A function (30,31). CYP3A enzyme is known to be expressed mainly in the liver and intestine, and both of them play important roles in drug metabolism.…”

Section: Discussionmentioning

confidence: 99%

Effects of Continuous Ingestion of Herbal Teas on Intestinal CYP3A in the Rat

et al. 2007

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Abstract. Tenryocha, rooibos, and guava teas are widely consumed as herbal beverages, especially as a therapy against pollen allergy. To investigate the possible herbal tea-drug interaction the effect of continuous ingestion of these teas on cytochrome P450 (CYP) 3A were studied. Rats (n = 6) were allowed free access to either tea (experimental groups) or water (control) for two weeks. Midazolam (MDZ) (20 mg / kg) was orally administered and the serum concentration was determined. The area under the serum concentration-time curve (AUC 0-∞ ) and the maximum serum concentrations (C max ) of MDZ were reduced by more than 60% after the treatment of tenryocha and rooibos tea (P<0.05). Intestinal MDZ 1'-and 4-hydroxylation activities mediated by CYP3A were increased in tenryocha and rooibos tea-treated group by 50% compared to the control group, although the results were not statistically significant. Furthermore, the Western blot analysis showed that CYP3A content was significantly increased in the intestine after the treatment of these teas (P<0.05). Hepatic MDZ hydroxylation and CYP3A content were slightly increased by these teas. The results suggested that two weeks ingestion of tenryocha and rooibos tea reduced serum concentration of MDZ by the induction of intestinal CYP3A. The possible interaction between tenryocha or rooibos tea and medicines mediated by CYP3A was suggested.

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Section: Discussionmentioning

confidence: 99%

Effects of Continuous Ingestion of Herbal Teas on Intestinal CYP3A in the Rat

et al. 2007

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“…Hepatic (ERH = CLiv/QH) and gastrointestinal extraction ratio (ERG = 1 − F/1 − ERH) were calculated assuming a liver blood flow (QH) of 25.4 ml min −1 × body weight (kg) × (1 − haematocrit) [16]. Bioavailability was calculated as follows:…”

Section: Pharmacokinetic Analysis and Statistical Evaluationmentioning

confidence: 99%

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Hohmann

Kocheise

Carls

et al. 2015

Brit J Clinical Pharma

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AIMWe aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. METHODSIn an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics. RESULTS Dose CONCLUSIONThe pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Midazolam pharmacokinetics of oral doses are linear over a 30 000-fold range.• An oral microdose of midazolam is suitable to measure total CYP3A activity.• CYP3A inhibition with strong inhibitors can be evaluated with a microdose in healthy volunteers and patients. WHAT THIS STUDY ADDS• The pharmacokinetics of intravenous midazolam microdoses are linear to milligram doses.• The bioavailability and metabolic clearance of midazolam is similar after administration of microdoses and milligram doses.• Midazolam microdoses are a suitable tool to assess both systemic and pre-systemic CYP3A activity.

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“…A complete search of the literature using the Metabolism and Transport Drug Interaction Database (University of Washington, Seattle, WA) indentified 11 clinical DDI studies and 16 dosage scenarios from 17 published clinical results using midazolam as CYP3A probe (intravenous and oral) and ketoconazole as inhibitor (400 mg QD and 200 mg QD and BID for various durations) as of 2012 (Olkkola et al, 1994;McCrea et al, 1999;Tsunoda et al, 1999;Goh et al, 2002;Lee et al, 2002;Lam et al, 2003;Eap et al, 2004;Chung et al, 2006;Tham et al, 2006;Yong et al, 2008;Krishna et al, 2009;Stoch et al, 2009). The specific treatment regimens of ketoconazole and midazolam used in the literature reports were reproduced in the simulations.…”

Section: Model Validation and Simulationmentioning

confidence: 99%

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

Han

Mao²,

Chien

et al. 2013

Drug Metab Dispos

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Ketoconazole is a potent CYP3A inhibitor used to assess the contribution of CYP3A to drug clearance and quantify the increase in drug exposure due to a strong inhibitor. Physiologically based pharmacokinetic (PBPK) models have been used to evaluate treatment regimens resulting in maximal CYP3A inhibition by ketoconazole but have reached different conclusions. We compare two PBPK models of the ketoconazole-midazolam interaction, model 1 (Chien et al., 2006) and model 2 implemented in Simcyp (version 11), to predict 16 published treatment regimens. With use of model 2, 41% of the study point estimates of area under the curve (AUC) ratio and 71% of the 90% confidence intervals were predicted within 1.5-fold of the observed, but these increased to 82 and 100%, respectively, with model 1. For midazolam, model 2 predicted a maximal midazolam AUC ratio of 8 and a hepatic fraction metabolized by CYP3A (f m ) of 0.97, whereas model 1 predicted 17 and 0.90, respectively, which are more consistent with observed data. On the basis of model 1, ketoconazole (400 mg QD) for at least 3 days and substrate administration within 2 hours is required for maximal CYP3A inhibition. Ketoconazole treatment regimens that use 200 mg BID underestimate the systemic fraction metabolized by CYP3A (0.86 versus 0.90) for midazolam. The systematic underprediction also applies to CYP3A substrates with high bioavailability and long half-lives. The superior predictive performance of model 1 reflects the need for accumulation of ketoconazole at enzyme site and protracted inhibition. Model 2 is not recommended for inferring optimal study design and estimation of fraction metabolized by CYP3A.

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Application of semisimultaneous midazolam administration for hepatic and intestinal cytochrome P450 3A phenotyping

Cited by 85 publications

References 27 publications

Effects of Continuous Ingestion of Herbal Teas on Intestinal CYP3A in the Rat

Effects of Continuous Ingestion of Herbal Teas on Intestinal CYP3A in the Rat

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Optimization of Drug-Drug Interaction Study Design: Comparison of Minimal Physiologically Based Pharmacokinetic Models on Prediction of CYP3A Inhibition by Ketoconazole

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