1 The effects of sex and oral contraceptives (OC) on the disposition of oral nitrazepam were studied in six healthy young males, in six healthy young females in the follicular and luteal phase of the menstrual cycle and in six healthy young females using OC-steroids in two stages of the pill cycle. 2 There was no influence of the menstrual cycle on the pharmacokinetic parameters of nitrazepam, nor was there a significant difference between these parameters in males and in females in either phase of the cycle. The elimination half-life was 27.3 + 1.3 h in males, 27.7 + 1.5 h in females in the follicular phase and 29.6 + 1.4 h in the luteal phase of the menstrual cycle. Total plasma clearance was 59.3 ± 2.7 ml/min, 58.2 + 3,3 and 55.8 ± 5.0 ml/min respectively. 3 The use of OC-steroids did not significantly alter the elimination half-life of nitrazepam: 30.6 + 2.3 and 31.2 + 2.2 h in the first and second half of the pill cycle. The total nitrazepam clearance in these females (46.6 + 4.6 and 45.6 ± 4.1 ml/min) was significantly lower than in males (P < 0.05). 4 The protein unbound fraction of nitrazepam was progressively higher going from males (11.4 ± 0.1%) to females in the luteal phase of the cycle (12.4 + 0.5%) to females using OC-steroids (13.5 ± 0.4%). Only the difference between males and females using OC-steroids was statistically significant. 5 The clearance calculated relative to the unbound drug (intrinsic clearance) was significantly decreased in females taking OC-steroids as compared to males and females not taking them (C; = 323 + 30 ml/min in females using OC-steroids, 530 + 37 ml/min in males and 459 + 40 ml/min in females). 6 The results of this study are not likely to have important consequences for dosage of nitrazepam as an hypnotic. The most pronounced effect observed was inhibition of nitrazepam clearance and especially intrinsic clearance by OC-steroids. Females on OC-steroids taking a nitrazepam tablet every evening, will have higher steady state levels of nitrazepam (and certainly of unbound nitrazepam) than males or females not taking OC-steroids.

Pharmacokinetics and bioavailability of brotizolam after i.v. and oral administration were studied in healthy young volunteers. Kinetic parameters after i.v. administration were: volume of distribution 0.66 +/‐ 0.19 1/kg, total plasma clearance 113 +/‐ 28 ml/min, distribution half‐life 11 +/‐ 6 min, and elimination half‐life 4.8 +/‐ 1.4 h (mean values +/‐ s.d.). Kinetic parameters after oral administration were: absorption lag‐time 8 +/‐ 12 min, absorption half‐life 10 +/‐ 11 min, and elimination half‐life 5.1 +/‐ 1.2 h (mean values +/‐ s.d.). Bioavailability of brotizolam was 70 +/‐ 22% when calculated by comparing oral and intravenous area‐under‐curve values, corrected for intra‐individual half‐life differences. An alternative calculation method, which is relatively independent of large clearance variations, provided a bioavailability of 70 +/‐ 24% (range: 47‐117%).

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To investigate how hepatic malfunction affects the disposition of hexobarbital (HB), an intermediate ‘high-clearance’ compound, and antipyrine (AP), a low-clearance compound, as well as the correlation between the rates of elimination of these drugs, their pharmacokinetics, were studied in control rats (n = 8) and in rats with a portacaval shunt (PCS; n = 9). Blood concentrations of parent drugs were measured, and urinary excretion of the following metabolites was determined: 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine and norantipyrine as primary metabolites of AP, and 3’-hydroxyhexobarbital (OH-HB) and 3’-ketohexobarbital (K-HB) as primary metabolites of HB.Blood elimination half-lives of AP and HB were more than four times longer in PCS rats than in control rats, increasing from 63.7 ± 3.9 to 291 ± 66 min, and from 20.1 ± 1.8 to 84.2 ± 7.6 min, respectively. Intrinsic clearance of HB (CL_{int, HB}) was 167 ± 19 ml/min/kg in controls and 27 ± 4 ml/min/kg in PCS rats (CLp_int, _HB). Intrinsic clearance of AP (CL_Mnt, ap) in control rats was 15.1 ± 0.7 ml/min/kg and 5.9 ± 0.7 ml/min/kg in PCS rats (CL_{pcs, AP}). PCS reduced clearance for production of metabolites (CL_Mn) of AP by 50%, but CL_Mn of HB metabolites was decreased by more than 80%. The CL_{int, AP}, CL_int,HB, CL_pcs,HB, CL_pcs,AP, and CL_Mn data were correlated. Total clearance correlated better in PCS rats than in control rats: r = 0.77 versus r = 0.10, respectively, thus suggesting a decrease in substrate selectivity under pathological conditions. CL_OH-HB+K-HB, reflecting the major metabolic pathway of HB, correlated most closely with CL_HMA in PCS (r = 0.91). Therefore, the underlying metabolic conversions of HB and AP may be mediated by the same or very similar forms of cytochrome P-450. Our results suggest that the predictive value of the model substrate approach is valid under pathological conditions.