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Comparative Study
, 79 (2), 278-85

Midazolam Microdose to Determine Systemic and Pre-Systemic Metabolic CYP3A Activity in Humans

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Comparative Study

Midazolam Microdose to Determine Systemic and Pre-Systemic Metabolic CYP3A Activity in Humans

Nicolas Hohmann et al. Br J Clin Pharmacol.

Abstract

Aim: We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam.

Methods: In 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-normalized AUC and Cmax were 37.1 ng ml(-1 ) h [95% CI 35.5, 40.6] and 39.1 ng ml(-1) [95% CI 30.4, 50.2] for the microdose and 39.0 ng ml(-1 ) h [95% CI 36.1, 42.1] and 37.1 ng ml(-1) [95% CI 26.9, 51.3] for the milligram dose. CLmet was 253 ml min(-1) [95% CI 201, 318] vs. 278 ml min(-1) [95% CI 248, 311] for intravenous doses and 1880 ml min(-1) [95% CI 1590, 2230] vs. 2050 ml min(-1) [95% CI 1720, 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [95% CI 20.0, 27.3] vs. 20.9% [95% CI 17.1, 25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [95% CI 0.39, 0.49] and 0.53 [95% CI 0.45, 0.63] and compared well with those for milligram doses (0.43 [95% CI 0.37, 0.49] and 0.61 [95% CI 0.53, 0.70]).

Conclusion: The 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.

Keywords: CYP3A; UPLC/MS/MS; microdosing; midazolam; phenotyping.

Figures

Figure 1
Figure 1
Plasma concentration−time curve (mean and 95% confidence interval) of midazolam after intravenous (circles) and oral (triangles) administration of milligram and microgram doses of midazolam to 16 healthy volunteers. Closed symbols represent microgram doses, open symbols milligram doses
Figure 2
Figure 2
Metabolic clearance (mean and 95% confidence interval) of midazolam to 1'-OH-midazolam after administration of intravenous (circles) and oral (triangles) microgram and milligram doses in 16 healthy volunteers. Closed symbols represent microgram doses, open symbols milligram doses. The insert shows the intra-individual correlation of the metabolic clearance after intravenous (circles) and oral (triangles) microgram and milligram doses. The dashed line indicates the line of identity (slope = 1)
Figure 3
Figure 3
Pharmacokinetic parameters of midazolam in 16 healthy volunteers after intravenous and oral administration of milligram and microgram doses. Each point represents one participant. Closed symbols represent microgram doses, open symbols milligram doses. (A) Mean and 95% confidence interval of bioavailability of microgram and milligram doses of midazolam. (B) Mean and 95% confidence interval of apparent oral clearances of oral midazolam. (C) Mean and 95% confidence interval of hepatic extraction ratios of midazolam milligram and microgram doses. Diamond represents outlier

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