OXIDATIVE VERSUS CONJUGATIVE BIOTRANSFORMATION OF TEMAZEPAM

Twenty‐four healthy volunteers, aged 21–59 years, received single 30 mg oral doses of the benzodiazepine hypnotic temazepam. Levels of intact temazepam were determined in multiple plasma samples drawn during 48 h after dosage. Intact temazepam, its direct glucuronide conjugate, and the conjugate of its demethylated (oxidized) metabolite oxazepam were measured in two consecutive 24‐h urine collections. Mean kinetic variables for temazepam in plasma were: peak plasma level (Cmax), 873 ng ml−1; time of peak, 1·36 h after dosage; volume of distribution, 0·961 kg−1; elimination half‐life, 9·9 h; clearance, 1·16 ml min−1 kg−1. Volume of distribution increased significantly with body weight (r = 0·67, p < 0·001), and Cmax decreased with weight (r = −0·58, p < 0·01). Only 0·2 per cent of the dose was excreted as intact temazepam, and negligible amounts as intact oxazepam. However, 39 per cent of the dose was recovered as temazepam glucuronide, and oxazepam glucuronide accounted for another 4·7 per cent of the dose. The remainder was not accounted for. Thus, a significant fraction of temazepam clearance occurs by direct glucuronide conjugation, with the conjugate temazepam glucuronide excreted in urine. A much smaller fraction undergoes parallel oxidation to form oxazepam, which is subsequently conjugated to oxazepam glucuronide and excreted in urine. Copyright © 1990 John Wiley & Sons, Ltd.