PHARMACOKINETICS AND EFFECTS ON EXERCISE HEART RATE OF PK 11195 (52028 RP), AN ANTAGONIST OF PERIPHERAL BENZODIAZEPINE RECEPTORS, IN HEALTHY VOLUNTEERS

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Abstract
Summary—PK 11195 (or 52028 RP; 1‐(2‐chlorophenyl)‐N‐methyl‐N‐(1‐methylpropyl)‐3‐isoquinoline carboxamide), an antagonist of the peripheral‐type benzodiazepine receptors which are coupled to calcium channels, was administered to 10 healthy volunteers in order to study the pharmacokinetics and cardiovascular effects of the drug. PK 11195 was randomly administered intravenously (10 mg) and orally in three single dosages (100, 200 and 400 mg). Placebo was only given orally. Heart rate and blood pressure were recorded at rest and during exercise tests which were performed at 0, 1, 3, 6 and 24 h after dosing on each study day.Summary—The results showed that after IV administration, PK 11195 was rapidly distributed in two or three open compartments. Its elimination T1/2was short (3.7 ± 3.0 h) with high interindividual variability. After oral ingestion the pharmacokinetics of PK 11195 were linear over the range of 100–400 mg single oral doses with a stable absolute bioavailability (33%). T1/2elimination was prolonged (7–12 h) and the presence of secondary increases in plasma concentration at 8–10 h and 22–24 h after drug absorption may have been related to enterohepatic cycling. No unchanged PK 11195 could be detected in urine. PK 11195 did not significantly modify heart rate and blood pressure at rest or during exercise and was well tolerated by the subjects. These data suggest a high inter‐individual variability in PK 11195 disposition with extensive metabolism in normal exercising volunteers.

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