Six healthy volunteers received single 2-and 4-mg doses of lorazepam by 5-min intravenous infusion, in tablet form by mouth in the fasting state, and by deltoid intramuscular injection in a six-way crmsover study. A seventh subject received the 4-mg iv, PO, and im doses. Concentrations of lorazepam and its glucuronide metabolite in multiple plasma samples and in all urine collected during 72 hr after each dose were determined by electron-capture GLC. Mean kinetic variables for intravenous lorazepam after 2-and 4-mg doses, respectively, were: volume of distribution ( V d ) , 1.14 and 1.30 liten/kg; elimination half-life ( t 1 /~) , 14.3 and 14.6 hr; total clearance, 1.05 and 1.10 ml/min/kg; and cumulative urinary excretion of lorazepam glucuronide, 81.1 and 82.3% of the dose. With the possible exception of v d , all kinetic variables were dose independent. Following a lag time averaging 15-17 min, absorption of oral lorazepam was first order, with apparent absorption half-life (t l/za) values averaging 40 (2-mg dose) and 22 (4-mg dose) min. Absorption was 91-95% complete. No lag times were observed after intramuscular injection of lorazepam; absorption was first order, with t 11% values averaging 12 (2-mg dose) and 19 (4-mg dose) min. The completeness of absorption was 83-100%. Absorption kinetics for both oral and intramuscular lorazepam were dose independent. Plasma t 1/26 for intact lorazepam was independent of dose and administration route. Keyphrases Lorazepam-pharmacokinetics and bioavailability in humans, various administration routes compared o Pharmacokinetics-lorazepam in humans, various administration routes compared 0 Bioavailability-lorazepam in humans, various administration routes compared 0 Benzodiazepines-lorazepam, pharmacokinetics and bioavailability in humans, various administration routes compared 1 Written informed consent was obtained. 2 SMA-PO. 3 Containing 0.02 ml of benzyl alcohol and 0.18 ml of polyethylene glycol; volume adjusted to 1.0 ml with propylene glycol.
The effect of propranolol on antipyrine clearance in humans was evaluated in six healthy volunteers who received single 1.4 to 1.5 g doses of intravenous antipyrine on two occasions. The first (control) antipyrine trial was without concurrent drug administration; the second trial was done during treatment with therapeutic doses of propranolol (40 mg every 4 to 6 hours). Antipyrine elimination half-life (t1/2), volume of distribution (Vd), and total clearance were determined after each trial. In all subjects isoproterenol sensitivity decreased markedly during propranolol treatment, indicating a high degree of beta blockade produced by the drug. Mean antipyrine t1/2 during the propranolol treatment period was significantly prolonged, and total clearance significantly reduced, over the control values. Twenty-four-hour urinary excretion of 4-hydroxyantipyrine, the major metabolite of antipyrine, likewise was reduced from 23.6% of the dose on the control trial to 14.8% of the dose during propranolol coadministration (0.1 less than P less than 0.2). Vd however, was nearly identical during both trials (0.62 L/kg). Thus propranolol prolongs the half-life and reduces the clearance or biotransformation rate of antipyrine, a drug whose clearance is independent of hepatic blood flow. Propranolol may influence the activity of hepatic microsomal enzymes responsible for drug hydroxylation.
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