Pharmacokinetics of the new benzodiazepine antagonist Ro 15‐1788 in man following intravenous and oral administration.

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Abstract
During clinical pharmacology studies with the benzodiazepine antagonist Ro 15‐1788 the pharmacokinetic characteristics of high intravenous doses (20 and 40 mg) and of an oral dose (200 mg) were examined in six healthy male volunteers. Ro 15‐1788 was rapidly and extensively distributed in the body with an apparent volume of distribution Vss of 1.06 l kg‐1. Elimination occurred rapidly by hepatic metabolism and the high plasma clearance of 1.14 l min‐1 resulted in a short elimination half‐life of less than 1 h. No difference in the disposition parameters calculated from the data after the 20 and 40 mg doses was observed reflecting a dose‐proportionality in the areas under plasma concentration‐time curves and unchanged distribution characteristics. Because the blood/plasma distribution coefficient is close to unity the disposition parameters obtained from plasma concentrations are similar to the corresponding parameters with reference to blood. Following oral administration of 200 mg the drug is rapidly absorbed. Peak levels were reached after 20‐90 min and were close to or even higher than the values after the 40 mg intravenous dose at the same time point. Due to the high hepatic extraction ratio the fraction reaching the systemic circulation unchanged was reduced to approximately 16% during the absorption step.