Studies on the Pharmacokinetics of Pinacidil in Healthy Volunteers

Analytical methods were developed for the determination of pinacidil and its major metabolite, pinacidil pyridine N-oxide, in serum and urine. Using these methods, the pharmacokinetics of pinacidil were studied following intravenous and oral administration of the drug to healthy volunteers. Additional pharmacokinetic studies included the effect of food on the absorption of pinacidil and the effects of chronic dosing with pinacidil in middle-aged, healthy volunteers. The final study was an investigation of a possible correlation between the 4-hydroxylation of debrisoquine, the N-oxidation of trimethylamine and the N-oxidation of pinacidil in Caucasian volunteers. Pharmacokinetic analysis was performed by means of computer programs written or amended by myself for use with a Commodore PET microcomputer and by using the nonlinear regression program BMDP. The major pharmacokinetic parameters of pinacidil in healthy volunteers were; Clearance = 32.3 ± 10.3L/h; Apparent Volume of Distribution = 102.9 ± 16.6 L. The serum elimination half-life of pinacidil was 2.4 ± 0.7h. Pinacidil was found to be cleared from the body primarily by hepatic clearance and to have a low to medium hepatic extraction ratio. Renal clearance was low and there was evidence that pinacidil is subject to tubular reabsorption. Little pinacidil was excreted unchanged in urine, less than 5% of the administered dose in 24h. The main metabolite was pinacidil pyridine N-oxide, which accounted for up to 80% of the dose excreted in urine in some subjects. Urinary excretion of metabolite was increased following oral administration of pinacidil and chronic dosing led to accumulation of the metabolite in serum. Concomitant administration of sustained-release pinacidil with food was found to increase pinacidil bioavailability and reduce intersubject variation in the maximum serum concentration of pinacidil. There was no correlation observed between the 4-hydroxylation of debrisoquine and the N-oxidation of pinacidil or between the N-oxidation of trimethylamine and the N-oxidation of pinacidil.

Name dc:type.qualificationname

PhD

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

De Montfort University

Year dc:date.issued

1988

Author dc:creator

• McBurney, Alan

Licence

• https://dora.dmu.ac.uk/bitstreams/fd6c8ab8-713b-4b9e-b51d-a9f81b35e869/download