Stereoselective metabolism and pharmacokinetics of disopyramide enantiomers in humans.
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.
Le Corre
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P
Laboratoire de Pharmacie, Galénique et Biopharmacie, Université de Rennes I, France.
Gibassier
D
D
Sado
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P
Le Verge
R
R
D000328:Adult; D004206:Disopyramide / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D006207:Half-Life; D006801:Humans; D008297:Male; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D013237:Stereoisomerism
D009961:Orosomucoid; D004206:Disopyramide