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ABSTRACT: Propiverine hydrochloride, oxybutynin hydrochloride and terodiline hydrochloride have both anticholinergic and antispasmodic effects, and are used for the management of urinary frequency and incontinence. The average standard therapeutic doses of these drugs differ greatly. We retrospectively analyzed their pharmacological effects with consideration given to muscarinic acetylcholine receptor binding affinities, anticholinergic activities, and inhibitory effects on KCl-induced contraction. Muscarinic acetylcholine receptor occupancies and the inhibitory ratios of the drugs for both acetylcholine-induced and KCl-induced contraction in a steady state after oral administration of standard doses were calculated based on pharmacokinetics and the receptor occupancy theory. The average muscarinic acetylcholine receptor occupancy and inhibitory ratio of acetylcholine-induced contraction were estimated to be 12.6+/-1.06% and 3.27+/-0.74%, respectively, with no significant differences found between the drugs for those parameters. A significant linear relationship was found between muscarinic acetylcholine receptor occupancy and the maximum ratio of increase in bladder urinary capacity. On the other hand, the inhibitory ratios of KCl-induced contraction varied from 0.01 to 0.48%. The present results suggest that muscarinic acetylcholine receptor occupancy is a principal determinant of the therapeutic effect of a drug used for treatment of urinary disturbance.
Biological & Pharmaceutical Bulletin 08/2007; 30(7):1297-300. · 1.66 Impact Factor
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ABSTRACT: 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-desethyloxybutynin ((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.
Biological & Pharmaceutical Bulletin 06/2007; 30(5):955-62. · 1.66 Impact Factor
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ABSTRACT: The transdermal delivery system (TDS) of oxybutynin (OXY) is widely used for the treatment of overactive bladder patients. This report aimed to assess the effect of external heating on the pharmacokinetics of OXY after transdermal administration. Franz-type diffusion cell experiments at room temperature, 36 and 45 degrees C were performed to estimate the permeations of OXY through human epidermal membrane with an isosorbide dinitrate (ISDN) formulation as a reference. The fluxes of OXY at 36 and 45 degrees C were only approximately 1.2-fold higher than that at room temperature, while those of ISDN with heating were more than 2.5 times as high as that without heating (p<0.001). These results indicate that the influence of heating on the permeation of OXY from the TDS of OXY may be minimal.
Biological & Pharmaceutical Bulletin 03/2007; 30(3):612-5. · 1.66 Impact Factor
