RT Journal Article
SR Electronic
T1 Stereoselective metabolism and pharmacokinetics of disopyramide enantiomers in humans.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 858
OP 864
VO 16
IS 6
A1 P Le Corre
A1 D Gibassier
A1 P Sado
A1 R Le Verge
YR 1988
UL http://dmd.aspetjournals.org/content/16/6/858.abstract
AB Metabolism, pharmacokinetics, and influence of alpha 1-acid glycoprotein (alpha 1-AGP) plasma levels on protein binding of (R)-(-) and (S)-(+)-disopyramide (DP) were compared, in six healthy subjects, at the steady state, after oral administration of 100 mg twice daily. 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 nonrenal clearance, i.e. hepatic metabolic 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 mean unbound renal clearance of (R)-(-)- and (S)-(+)-mono-N-dealkylated disopyramide (MND) were 3.21 and 7.02 ml/min/kg, respectively (p less than 0.001). The unbound fraction at steady state of (R)-(-)-DP and (S)-(+)-DP averaged 12.5 and 7.5%, respectively (p = 0.002). The unbound fraction at steady state of (R)-(-)-DP and (S)-(+)-MND averaged 62.6 and 60.5%, respectively (p = 0.36). The highest alpha 1-AGP plasma concentration resulted in lower unbound fraction for both DP and MND enantiomers, whereas the lowest alpha 1-AGP plasma concentration resulted in higher unbound fraction for (S)-(+)-DP only.