Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats(Biopharmacy)

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To elucidate the relationships between the pharmacokinetics and pharmacological effects of oxybutynin ((R/S)-OXY), the micturition pressure and the plasma concentration profiles -of (R)-OXY and (R)-N-desethyloxy-butynin ((R)-DEOB), a pharmacologically active metabolite, after administration by three different routes (i.v., p.o. and transdermal) in rats were measured and analyzed using an inhibitory effect E_<max> model with their in vitro pharmacological effects. The plasma exposure ratios of (R)-DEOB to (R)-OXY calculated from the AUCS were somewhat different among the routes administered. (R)-OXY and (R)-DEOB equally inhibited the acetylcholine-induced contractions in vitro. The micturition pressure, measured using the cystometric method in vivo, exhibited saturation against the dose administered. The inhibitory effect E_<max> model well described the relationship between the micturition pressure and the receptor occupancy calculated from the plasma concentrations and pA_2 values and resulted in an extremely small receptor occupancy (0.206%) to exhibit half of the maximum effect. The estimated receptor occupancy profiles suggested a sufficient and long-lasting receptor occupation after transdermal administration of (R/S)-OXY, while the receptor occupancy diminished rapidly after the i.v. and p.o. administration. These data indicate that transdermal administration of (R/S)-OXY would be useful to achieve suitable pharmacological effects without excess plasma concentrations.
公益社団法人日本薬学会の論文
2007-05-01

Pharmacokinetics/Pharmacodynamics Analysis of the Relationship between the in Vivo Micturition Pressure and Receptor Occupancy of (R)-Oxybutynin and Its Metabolite in Rats(Biopharmacy)

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