PHARMACOKINETICS OF DILEVALOL AND ITS CONJUGATES IN MAN - ASSAY-METHOD FOR PLASMA, BLOOD, URINE AND BILE SAMPLES AND PRELIMINARY PHARMACOKINETIC STUDIES

The renal and biliary excretion of the beta-adrenoceptor blocking agen t dilevalol (CAS 75659-07-3) and its conjugates was examined in a prel iminary pharmacokinetic study. Plasma, urine and bile dilevalol concen trations were determined with a simplified procedure that is based on alkaline liquid-liquid extraction using diethyl ether and subsequent r eversed-phase HPLC separation of the reconstituted samples (on a PRP-1 stationary phase using a mixture of methanol and pH 9.8 carbonate buf fer as mobile phase). Triamterene was used as internal standard. The q uantification of the conjugates was accomplished indirectly via enzyma tic hydrolysis (glusulase) with and without addition of the beta-glucu ronidase inhibitor 1,4-saccharolactone (at a final concentration of 5. 5 mmol/l). In the pharmacokinetic study healthy volunteers and cholect ystectomised patients with a T-drain received a single oral dose of 20 0 mg dilevalol. Furthermore, to healthy volunteers an i.v. dose of 60 mg dilevalol was given in order to estimate the absolute bioavailabili ty. From the obtained data the systemic plasma clearance was calculate d to be 1708 ml/min. The oral bioavailability was calculated to be 16% . The log concentration-time curves of the metabolites paralleled thos e of dilevalol in the terminal section with average terminal half-live s of approx. 5h. In volunteers the fractions of the dose excreted rena lly were 0.5% for parent drug, 23% for the glucuronide(s) and 8% for t he sulfate. The corresponding values found for the patients were not s ignificantly different. In the patients' bile only 1.2% of the total d ose were found (0.03% dilevalol, 1.1% dilevalol glucuronide(s), 0.1% d ilevalol sulfate). The total fraction of the p.o. dose excreted in uri ne and bile - either as dilevalol or as conjugate - amounted to 30. It was hence concluded that formation of phase-I-metabolites must be an important clearance pathway.