Human pharmacokinetics and metabolism of disopyramide enantiomers.

The objective of the present study was to investigate human pharmacokinetics and metabolism of disopyramide (DP) enantiomers. Six healthy male volunteers entered the study. They were given, separately and via oral route, as repeated doses for 5 days, R(-) DP and S(+) DP at a dose of 100 mg twice daily. Unbound fractions of DP and metabolite (MND) enantiomers were obtained on each plasma sample, i.e. ex vivo, using ultrafiltration. Pharmacokinetic parameters of DP enantiomers based on total plasma concentrations were not significantly different. On the other hand, unbound pharmacokinetic parameters displayed marked stereoselectivity. The mean unbound clearance of R(-) DP and S(+) DP were 8.59 and 14.9 ml/min/kg, respectively (p = 0.003). The mean unbound renal clearance of R(-) DP and S(+) DP were 6.26 and 8.75 ml/min/kg, respectively (p = 0.025). The non renal clearance of R(-) DP and S(+) DP averaged 2.32 and 6.19 ml/min/kg, respectively (p = 0.002). The mean unbound volume of distribution of R(-) and S(+) DP were 225 and 381 liters, respectively (p = 0.023). The half-life of R(-) DP and S(+) DP averaged 4.17 and 3.91 hr, respectively (p = 0.21). The unbound fraction at steady-state of R(-) DP and S(+) DP averaged 12.5 and 7.5%, respectively (p = 0.002). In vitro binding experiments, performed for each subject, allowed to indicate that the stereoselective plasma binding was due to a stereoselective affinity, the binding capacity of both enantiomers being the same. Pharmacokinetic data emphasized the influence of stereoselectivity in the human disposition of DP enantiomers.(ABSTRACT TRUNCATED AT 250 WORDS)