Physiologie and temporal variation in hepatic elimination of midazolam

1 The potential for a drug interaction between cyclosporin A and midazolam was investigated since both compounds appear to be metabolized by the same cytochrome P-450 isoenzyme. 4 The pharmacokinetics of a single intravenous dose of midazolam (0.075 mg kg-') was studied in nine patients receiving cyclosporin A to prevent rejection of their transplanted kidneys. The average steady state blood concentrations of cyclosporin A, measured by r.i.a. using a specific monoclonal antibody, varied during a dosing interval between 175 and 600 ng ml-'.5 In these patients the hepatic elimination of midazolam was characterized by a mean t½, (± s.d.) of 2.3 ± 1.2 h and a plasma clearance (CL) of 414 ± 95 ml min-'. These values were not different from those of normal human subjects (t,, = 1.5 to 4 h, CL = 350 to 700 ml min-').6 From the results of the in vitro experiments it is concluded that cyclosporin A may potentially inhibit drug metabolism. However, therapeutic blood concentrations in vivo do not appear to be sufficient to result in an effective impairment of the hepatic elimination of midazolam when given concomitantly.

Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Spectrophotometric Analysis Of Microsomal Cytochrome P-450mentioning

confidence: 99%

See 1 more Smart Citation

Is cyclosporin A an inhibitor of drug metabolism?

Treiber

Meinshausen

et al. 1990

“…Maximum plasma concentrations were reached within the first hour after application in (Klotz & Ziegler 1982). Therefore, it is possible, that the discordant clearances observed in this study reflect different posture of the subjects.…”

Section: Discussionmentioning

confidence: 82%

Pharmacokinetics of midazolam and alpha‐hydroxy‐midazolam following rectal and intravenous administration.

Clausen

Wolff

et al. 1988

1 In an open cross-over trial, plasma concentrations of midazolam were measured in eight healthy male volunteers following administration of 0.3 mg kg-' body weight given by the rectal and intravenous routes.2 Maximumplasma concentrations of 92-156 ng ml-' (mean 118 ng ml-) were recorded from 20 to 50 min (mean 31 min) after rectal application. The rectal bioavailability was 40-65% (mean 52%) and the terminal half-life was 114-305 min (mean 161 min). 3 A substantial first-pass hepatic effect was observed following rectal administration. 4 No systemic or local intolerance was noted. 5 In conclusion, the rectal route of administration provides a rapid and reliable absorption of midazolam.

“…Midazolam pharmacokinetics was determined by noncompartmental analysis (WinNonlin v3.1; Pharsight, Cary, NC, USA). Sample size calculations were based on previously published data [5,[8][9][10]. Using an a = 0.05 and b = 0.20, a sample size of 12 would detect a 25% difference in midazolam CL.…”

Section: Intravenousmentioning

confidence: 99%

Lack of effect of subject posture on intravenous midazolam clearance: implications for hepatic cytochrome P450 3A phenotyping

Joseph

Nafziger

Mylott

et al. 2009

Intravenous (i.v.) midazolam is used to phenotype hepatic cytochrome P450 (CYP) 3A [1]. Midazolam clearance (CL) is believed to correlate with the intrinsic hepatic CL (CLint) of midazolam and thus acts as a surrogate for hepatic CYP3A activity. Midazolam is a moderate extraction ratio drug [2]. Based on the well-stirred model of hepatic clearance [3], midazolam CL depends on CLint and hepatic blood flow. Subject posture alters hepatic blood flow, is often not controlled during blood sample collection [1], and impacts pharmacokinetic studies [4]. The magnitude of postureinduced blood flow changes has been seen in a study of six subjects. Plasma midazolam CL decreased 48% in an ambulant (sitting/walking) posture compared with a supine posture [5] and suggests that changes in midazolam CL may be dependent on hepatic blood flow and not exclusively CYP3A activity. This study evaluated the effect of subject posture on midazolam CL to confirm previous findings. We quantified posture-induced hepatic blood flow changes with i.v. indocyanine green as a biomarker. Results are published elsewhere [6].The Institutional Review Board of Bassett Healthcare (Cooperstown, NY, USA) approved the study. Written informed consent was obtained. Healthy adults 18-55 years old who were not on any medications were enrolled. Subjects were randomized to a 7-h supine or ambulant posture. A minimum of 7 days passed between study phases. Subjects maintained strict horizontal bed rest during supine posture. During ambulant posture, subjects were seated for the first 3 h and then allowed to stand, walk, or sit. Sessions began between 06.00 h and 07.00 h to minimize temporal variation [5]. Subjects fasted (except water) overnight and for the duration of each posture. To stabilize hepatic blood flow, subjects were in the assigned posture for 1 h prior to midazolam 0.025 mg kg -1 i.v. (midazolam hydrochloride, 1 mg ml -1 injection, North Chicago, IL, USA) administration. Eight blood samples were obtained over 6 h. Samples were centrifuged and stored at -80°C. Plasma concentrations were analysed by liquid chromatography/mass spectrometry/mass spectrometry as described elsewhere [7]. The linear range of the assay was 0.50-100 ng ml -1 , with intra-and interday coefficients of variation of Յ7.9% at 0.75, 7.5 and 75 ng ml -1 . Midazolam pharmacokinetics was determined by noncompartmental analysis (WinNonlin v3.1; Pharsight, Cary, NC, USA). Sample size calculations were based on previously published data [5,[8][9][10]. Using an a = 0.05 and b = 0.20, a sample size of 12 would detect a 25% difference in midazolam CL. Bioequivalence testing was used by calculating the least squares geometric mean ratios (LS-GMR; CLambulant/CLsupine) and 90% confidence intervals (CI). Bioequivalence was concluded if the 90% CIs were within the 80-125% interval.Thirteen (seven female) subjects completed both postures. Plasma midazolam concentrations vs. time are shown in Figure 1. Bioequivalence was observed for the geometric mean midazolam CLs in the supine and ambulant ...