Influence of Food on Midazolam Absorption

Bornemann, L. D.; Crews, Theodore; Chen, Susan S.; Twardak, Stefan; Patel, Indravadan H.

doi:10.1002/j.1552-4604.1986.tb02903.x

Cited by 29 publications

(24 citation statements)

References 14 publications

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“…Food intake increases blood flow in the gut and liver, and may affect the first-pass metabolism. A previous study reported a small but significant decrease in the bioavailability of midazolam when the drug was given 1 h after a meal [17]. Food intake may partly contribute to the difference in results between the current study and the other earlier studies.…”

Section: Discussioncontrasting

confidence: 86%

The recovery time‐course of CYP3A after induction by St John's wort administration

Imai¹,

Kotegawa²,

Tsutsumi³

et al. 2008

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • St John's wort causes the induction of CYP3A. Little is known about how long the effect remains after cessation of St John's wort. WHAT THIS STUDY ADDS • The in vivo CYP3A activity returns progressively to the basal level approximately 1 week after cessation of St John's wort administration AIMS To examine the recovery time course of CYP3A after enzyme induction by St John's wort administration. METHODS The subjects were 12 healthy men, aged 20–33 years. On the first day, they received an oral dose of midazolam 5 mg without St John's wort (day −14). From the next day, they took St John's wort for 14 days. On the last day of St John's wort treatment (day 0) and 3 and 7 days after completion of St John's wort treatment (days 3 and 7), they received the same dose of midazolam. On each day, blood samples were obtained until 8 h after midazolam administration. Plasma concentrations of midazolam were measured by HPLC. Pharmacokinetic parameters of midazolam were determined using noncompartmental analysis. RESULTS Apparent oral clearance of midazolam was significantly increased after St John's wort administration from 65.3 ± 8.4 l h−1 (day −14) to 86.8 ± 17.3 l h−1 (day 0). It returned to the control level 7 days after the completion of St John's wort (day 7, 59.7 ± 3.8 l h−1). No significant difference in the elimination half‐life between the four periods of the study was observed. The changes in apparent oral clearance after St John's wort discontinuation indicated that CYP3A activity recovers from enzyme induction with an estimated half‐life of 46.2 h. CONCLUSIONS CYP3A activity induced by St John's wort administration progressively returns to the basal level after approximately 1 week. This finding may provide useful information to avoid clinically significant interactions of St John's wort with CYP3A substrates.

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Section: Discussioncontrasting

confidence: 86%

The recovery time‐course of CYP3A after induction by St John's wort administration

Imai¹,

Kotegawa²,

Tsutsumi³

et al. 2008

Brit J Clinical Pharma

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“…However, identifying an optimal midazolam sampling time a priori is confounded by several variables. Each of the following can affect the optimal time predicted for midazolam sampling: intersubject heterogeneity in CYP3A activity, CYP3A modulation by concomitant medications, route of midazolam administration (oral vs intravenous), and possibly food consumption with oral midazolam 14 , 15 . In addition, a single‐sequence study design, such as that employed in the current investigation, could theoretically affect midazolam concentration measurements; however, we believe the chances of this occurring are minimal given that midazolam has not been shown to affect CYP3A expression or activity.…”

Section: Discussionmentioning

confidence: 99%

Limitations of Using a Single Postdose Midazolam Concentration to Predict CYP3A‐Mediated Drug Interactions

Penzak

Busse

Robertson

et al. 2008

The Journal of Clinical Pharma

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Midazolam is a common probe used to predict CYP3A activity, but multiple blood samples are necessary to determine midazolam's area under the concentration-time curve (AUC). As such, single sampling strategies have been examined. The purpose of this study was to assess the ability of single midazolam concentrations to predict midazolam AUC in the presence and absence of CYP3A modulation by Ginkgo biloba extract (GBE). Subjects received oral midazolam 8 mg before and after 28 days of GBE administration. Postdose blood samples were collected during both study periods and midazolam AUC determined. Linear regression was used to generate measures of predictive performance for each midazolam concentration. The geometric mean ratio (90% confidence intervals) of midazolam AUC 0-∞ post-GBE/AUC 0-∞ pre-GBE was 0.66 (0.49-0.84) (P = .03). Before and after GBE administration, optimal midazolam sampling times were identified at 3.5 to 5 hours and 2 to 3 hours, respectively. Single midazolam concentrations between 2 and 5 hours correctly predicted the reduction in midazolam AUC following GBE exposure, but confidence intervals were generally wide. Intersubject variability in CYP3A activity (either inherent or from drug administration) alters the prediction of optimal midazolam sampling times; therefore, midazolam AUC is preferred for assessing CYP3A activity in drug-drug interaction studies. Keywords Midazolam; Ginkgo biloba extract; drug interactions; CYP3ACytochrome P 450 (CYP) is a large group of enzymes responsible for phase I oxidative metabolism. CYP enzymes are located in various tissues throughout the body, with the liver being the largest source. Two intestinal CYP isoforms that account for approximately 70% of total intestinal CYP activity include CYP3A4 and CYP3A5. Because >50% of CYPmetabolized drugs are substrates for CYP3A, modulation of this enzyme is the source of numerous drug-drug interactions. 1 However, it is not practical to study each CYP3A substrate to determine its interaction potential with CYP3A-modulating medications. As such, various CYP3A probe drugs have been identified to detect and quantify potential CYP3A-mediated drug-drug interactions. 2Midazolam has been used extensively as a probe for determining CYP3A4 and 3A5 catalytic activity in vivo; it is metabolized by CYP3A4 and CYP3A5 to its primary metabolite, 1′- The purpose of this healthy volunteer study was to assess the ability of single postdose midazolam concentrations to independently predict CYP3A activity as determined by midazolam area under the concentration-time curve (AUC), in the presence and absence of a newly described CYP3A-modulating compound, and to assess potential limitations associated with this approach. This study was a nested substudy of a larger investigation that examined the influence of Ginkgo biloba leaf extract (GBE) on the pharmacokinetics of the HIV protease inhibitor combination lopinavir/ritonavir. NIH Public Access METHODS Study SubjectsTo be considered for study inclusion, subjects had to be 18 to 50 y...

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“…18,19,35,45 Thus MDZ clearance can be influenced by changes in hepatic blood flow, as well as by changes in metabolism, and differences in hepatic blood flow have been shown to contribute to variability in MDZ clearance. [19][20][21] ALF is a more selective probe for changes in hepatic intrinsic clearance. In contrast to differences in hepatic extraction, MDZ (46%) and ALF (44%) underwent identical intestinal extraction.…”

Section: Discussionmentioning

confidence: 99%

Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: Noninvasive assessment by use of pupillary miosis

Kharasch¹,

Walker²,

Hoffer³

et al. 2004

Clinical Pharmacology & Therapeutics

111

134

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Influence of Food on Midazolam Absorption

Cited by 29 publications

References 14 publications

The recovery time‐course of CYP3A after induction by St John's wort administration

The recovery time‐course of CYP3A after induction by St John's wort administration

Limitations of Using a Single Postdose Midazolam Concentration to Predict CYP3A‐Mediated Drug Interactions

Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: Noninvasive assessment by use of pupillary miosis

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