Pharmacokinetics of picumast dihydrochloride and its active metabolites M1 and M2 in humans

The pharmacokinetics of picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) and the pharmacodynamically active metabolites M1 and M2 as well as the absolute bioavailability of picumast dihydrochloride have been studied in healthy volunteers after oral administration of the drug in doses which were considerably higher than therapeutically used. After intravenous administration of 10 mg picumast dihydrochloride a peak concentration of 182 ng/ml was achieved at the end of the 1 h infusion. Picumast dihydrochloride was extensively distributed to the tissues (Vz = 130 l) and almost exclusively eliminated by hepatic metabolism (total clearance 95 ml/min, amount of unchanged compound excreted in urine below detection limit). Median elimination half-life was 16.5 h. The absolute bioavailability reached 57%. The relative bioavailability of picumast dihydrochloride was 20% higher after a meal. After a 20 mg oral dose maximum concentrations between 129 and 284 ng/ml were achieved within 1.3 h. The elimination half-life ranged from 10-26 h. No difference existed between oral (14.5 h) and intravenous administration. The metabolites M1 and M2 in human plasma peaked at 3.4 and 4 h. With 41 h (M1) and 34 h (M2) they exhibited longer half-lives than the parent compound. So under steady state conditions the average plasma concentration of these metabolites amounted to about 68% and 40%, resp., of the unchanged drug as calculated by the ratio of the total areas. The total amount of metabolites M1 and M2 recovered in urine was 6.88% of the oral dose administered, i.e. 6.8% M1 and 0.08% M2. The renal clearance was determined as 28 and 0.5 ml/min for M1 and M2, resp.