Pharmacokinetics of brotizolam in healthy subjects following intravenous and oral administration.

Abstract

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%).

Comparative pharmacokinetics of brotizolam and triazolam in healthy subjects.

“…Clinically, a rapid rate of absorption is important for a hypnotic as such drugs are frequently prescribed for patients who experience difficulties 5.0 ± 1.1 2.6 ± 0.7 (Breimer, 1979;. In another study it was also shown that brotizolam absorption may not be complete (Jochemsen et al, 1983) (Jochemsen et al, 1983). For triazolam, an estimate of these parameters can be made using the data shown in Table 3, assuming that liver blood flow is approximately 21 ml/min/kg, that the haematocrit is approximately 0.5 and that the partition coefficient of triazolam between blood and plasma is about zero (Jochemsen, unpublished results;Rowland, 1972 (Amrein et al, 1981).…”

“…A major problem with triazolam and brotizolam is the intraindividual variability in elimination half-life. For brotizolam it is likely that this is almost entirely due to variability in clearance (Jochemsen et al, 1983). …”

“…It has elimination half-lives in the range of 1.5-3.5 h (Eberts et al, 1981;. Brotizolam (Lendormin®), a 1,4-thienodiazepine, has half-lives in the range of 3-6 h (Jochemsen et at., 1983). They are metabolized by the same pathways: the major metabolites are the 1-methylhydroxy-and the 4-hydroxy-derivatives.…”

Brotizolam as a pre‐operative hypnotic.

“…Further, though residual activity the next day is not detrimental in major surgery, a persistent aftereffect with the possibility of interaction with the anaesthetic agents may be disadvantageous for minor operations. With these criteria in mind the suitability of a rapidly eliminated hypnotic, brotizolam (Lendormin®) (Bechtel, 1983;Jochemsen et al, 1983), was studied.…”

Pharmacokinetics of oral brotizolam in patients with liver cirrhosis.

“…It is inactivated in the human body through biotransformation, the primary steps being hydroxylation in the 1-methyl-and the 4-position (Boehringer Ingelheim, product information). The elimination half-life of brotizolam is relatively short (3-6 h) in young healthy subjects (Jochemsen et al, 1983a). It was demonstrated recently that the kinetics of brotizolam are considerably influenced by age: the mean elimination half-life in the elderly subjects was twice as long as in young subjects.…”