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Pharmacokinetics of CGP 36 742, an Orally Active GABAB Antagonist, in Humans

A study was conducted to evaluate the pharmacokinetics of CGP 36 742 (3‐aminopropyl‐n‐butyl‐phosphinic acid), an orally active γ‐aminobutyric acid B (GABAB) antagonist, in humans. Pharmacokinetic results after a single oral (600 mg) dose included maximum observed concentration (Cmax), 27 μmol/L (95% CI 22.9, 30.8); time to Cmax (tmax), 3 hours (median); half‐life (t1/2), 3.6 hours (95% CI 3.24, 3.9); renal clearance (CIR), 125 mL/min (95% CI 114, 136); and absolute bioavailability (Fabs), 0.44 (95% CI 0.33, 0.47). Administration with food decreased the oral systemic availability (Fre) by 30%. The volume of distribution (285 L/kg) was in the order of magnitude of extracellular body water. The absorbed fraction of the compound was excreted completely and unchanged via the kidney, thus renal function would be the limiting factor for excretion. The rate of absorption and amount absorbed did not differ significantly between elderly and young healthy male volunteers, both after single and multiple doses. There was no gender‐related difference in pharmacokinetics in healthy elderly volunteers. CGP 36 742 showed an excellent safety profile: there were no clinically relevant changes in cardiovascular variables, body temperature, or blood chemistry. In the placebo‐controlled trial, adverse experiences were rare and evenly distributed among participants receiving placebo and the study drug. In addition, a newly developed high‐performance liquid chromatography (HPLC) method for measurement of CGP 36 742 concentrations in plasma and urine using fluorescence detection is described.