Intravesical oxybutynin for neurogenic bladder dysfunction:: Less systemic side effects due to reduced first pass metabolism
Intravesical oxybutynin for neurogenic bladder dysfunction:: Less systemic side effects due to reduced first pass metabolism
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DOI：
10.1016/s0022-5347(01)62828-3
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发表时间：
1998-09-01
影响因子：
6.6
通讯作者：
Andersson, KE
中科院分区：
文献类型：
--
作者：
Buyse, G;Waldeck, K;Andersson, KE
目的：为了解释为什么膀胱内注射奥施布宁比口服奥施布宁治疗神经源性膀胱功能障碍更有效，而且全身副作用明显少，我们检验了奥施布宁膀胱内注射后吸收和代谢发生改变的假设。材料与方法：建立了高效液相色谱法测定奥施布宁及其活性代谢物n -去乙基奥施布宁。在稳态条件下，对儿童经膀胱（n = 11）和口服（n = 5）施用奥施布宁后的血浆浓度进行量化。计算药代动力学参数。结果：口服奥氧布宁0.2 mg,/kg；/剂量)导致n -去乙基-奥施布宁的血药浓度峰值是奥施布宁相应值的7.4 +/- 1.3倍（n 5）。去乙基奥施布宁的AUC（血药浓度时间曲线下面积）值也高于奥施布宁，比值为10.8 +/- 1.0 （n = 5）。膀胱内滴注（0.2 mg./kg）。另一方面，n -去乙基-奥施布宁的代谢物生成减少，血浆峰值浓度与奥施布宁在相同的范围内，比值为1.2 +/- 0.1 （n = 11）。n -去乙基-奥施布宁与奥施布宁的AUC比值为2.1 +/- 0.2 （n = 11）。结论：与母体化合物相比，n -去乙基代谢物的AUC比显著降低，这可能解释了与口服奥施布宁治疗相比，膀胱内副作用的临床相关减少。
Purpose: 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.Materials and Methods: 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.Results: 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).Conclusions: 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.