Buyse G, Waldeck K, Verpoorten C, Björk H, Casaer P, Andersson K E
Department of Paediatrics, University Hospital Gasthuisberg, Leuven, Belgium.
J Urol. 1998 Sep;160(3 Pt 1):892-6. doi: 10.1016/S0022-5347(01)62828-3.
To unravel why intravesical oxybutynin is more effective and causes significantly fewer systemic side effects than oral oxybutynin in the treatment of neurogenic bladder dysfunction, we tested the hypothesis that the absorption and metabolism of oxybutynin are changed after intravesical instillation.
A high-performance liquid chromatography assay was developed for both oxybutynin and its active metabolite, N-desethyl-oxybutynin. Plasma concentrations were quantified after intravesical (n = 11) and oral (n = 5) administration of oxybutynin in children under steady-state conditions. Pharmacokinetic parameters were calculated.
Oral administration of oxybutynin (0.2 mg./kg./dose) resulted in peak plasma concentrations for N-desethyl-oxybutynin which were 7.4 +/- 1.3 times higher than corresponding values for oxybutynin (n = 5). Also the AUC (area under the plasma concentration time curve) values were higher for N-desethyl-oxybutynin compared with those of oxybutynin, the ratio being 10.8 +/- 1.0 (n = 5). Intravesical instillation (0.2 mg./kg./dose), on the other hand, resulted in reduced metabolite generation and peak plasma concentrations for N-desethyl-oxybutynin which were in the same range as those for oxybutynin, the ratio being 1.2 +/- 0.1 (n = 11). The ratio for the AUC values for N-desethyl-oxybutynin and oxybutynin was 2.1 +/- 0.2 (n = 11).
The significantly lower AUC ratio of the N-desethyl metabolite over the mother compound, due to a reduced first pass metabolism, may explain the clinically relevant reduction of side effects that characterizes intravesical compared with oral oxybutynin therapy.
为了阐明为何膀胱内注射奥昔布宁在治疗神经源性膀胱功能障碍方面比口服奥昔布宁更有效且引起的全身副作用显著更少，我们验证了以下假设：膀胱内滴注后奥昔布宁的吸收和代谢会发生改变。
开发了一种高效液相色谱分析法，用于检测奥昔布宁及其活性代谢物N - 去乙基奥昔布宁。在稳态条件下，对儿童进行膀胱内（n = 1）和口服（n = 5）奥昔布宁给药后，对血浆浓度进行定量分析。计算药代动力学参数。
口服奥昔布宁（0.2 mg./kg./剂量）导致N - 去乙基奥昔布宁的血浆峰值浓度比奥昔布宁的相应值高7.4 +/- 1.3倍（n = 5）。同样，N - 去乙基奥昔布宁的AUC（血浆浓度 - 时间曲线下面积）值也高于奥昔布宁，比值为10.8 +/- 1.0（n = 5）。另一方面，膀胱内滴注（0.2 mg./kg./剂量）导致代谢物生成减少，N - 去乙基奥昔布宁的血浆峰值浓度与奥昔布宁处于同一范围，比值为1.2 +/- 0.1（n = 11）。N - 去乙基奥昔布宁与奥昔布宁的AUC值之比为2.1 +/- 0.2（n = 11）。
由于首过代谢减少，N - 去乙基代谢物与母体化合物的AUC比值显著降低，这可能解释了与口服奥昔布宁治疗相比，膀胱内注射奥昔布宁在临床上副作用减少的相关性。
