Gupta S K, Sathyan G
Alza Corporation, Palo Alto, CA, USA.
J Clin Pharmacol. 1999 Mar;39(3):289-96.
Oxybutynin is used for the treatment of urge urinary incontinence. In this randomized, open-label, two-way crossover, multiple-dose study, the pharmacokinetics of a once-daily, controlled-release formulation, OROS oxybutynin chloride, was compared with that of immediate-release (IR) oxybutynin (Ditropan). Thirteen healthy female volunteers received three 5 mg OROS oxybutynin chloride tablets once daily for 4 days or IR oxybutynin 5 mg administered every 8 hours for 4 days. On day 1, with OROS oxybutynin chloride, mean plasma concentrations rose slowly over approximately 6 hours following dosing (mean Cmax 4.2 ng/mL) and remained fairly constant over the 24-hour dosing interval, whereas with IR oxybutynin, mean plasma concentrations rose rapidly within the first hour after dosing (mean Cmax 12.0 ng/mL), then declined. The mean oxybutynin degree of fluctuation was much lower for OROS oxybutynin chloride (78%) than for IR oxybutynin (371%). For both formulations, the plasma concentration-time profiles for the metabolite N-desethyloxybutynin paralleled those of oxybutynin but at higher concentrations. Steady-state oxybutynin concentrations were achieved by day 3 for both formulations. Mean area under the concentration-time curve (AUC) values for both oxybutynin and its metabolite were similar between day 1 and day 4 for each treatment, suggesting time-invariant pharmacokinetics. With OROS oxybutynin chloride, mean relative bioavailability was higher (153%) for oxybutynin and lower (69%) for N-desethyloxybutynin compared with IR oxybutynin. This increased bioavailability may be due to reduced first-pass metabolism; within 3 to 5 hours after dosing, OROS systems are thought to reach the colon, where cytochrome P450-mediated oxidation (oxybutynin's primary metabolic pathway) may be less extensive than in the small intestine. Fewer subjects reported any adverse event with OROS oxybutynin chloride than with IR oxybutynin (including dry mouth, oxybutynin's most frequently reported anticholinergic adverse effect).
奥昔布宁用于治疗急迫性尿失禁。在这项随机、开放标签、双向交叉、多剂量研究中，将每日一次的控释制剂奥昔布宁氯（OROS）的药代动力学与速释（IR）奥昔布宁（Ditropan）进行了比较。13名健康女性志愿者每天服用3片5毫克奥昔布宁氯片，共4天，或每8小时服用5毫克IR奥昔布宁，共4天。第1天，服用奥昔布宁氯后，平均血浆浓度在给药后约6小时内缓慢上升（平均Cmax为4.2纳克/毫升），并在24小时给药间隔内保持相当稳定，而服用IR奥昔布宁后，平均血浆浓度在给药后第一小时内迅速上升（平均Cmax为12.0纳克/毫升），然后下降。奥昔布宁氯的平均波动度（78%）远低于IR奥昔布宁（371%）。对于两种制剂，代谢物N-去乙基奥昔布宁的血浆浓度-时间曲线与奥昔布宁平行，但浓度更高。两种制剂在第3天均达到稳态奥昔布宁浓度。每种治疗在第1天和第4天，奥昔布宁及其代谢物的平均浓度-时间曲线下面积（AUC）值相似，表明药代动力学不随时间变化。与IR奥昔布宁相比，奥昔布宁氯的奥昔布宁平均相对生物利用度更高（153%），N-去乙基奥昔布宁更低（69%）。这种生物利用度的提高可能是由于首过代谢减少；给药后3至5小时内，OROS系统被认为到达结肠，在结肠中细胞色素P450介导的氧化（奥昔布宁的主要代谢途径）可能不如在小肠中广泛。与IR奥昔布宁相比，报告任何不良事件的服用奥昔布宁氯的受试者更少（包括口干，这是奥昔布宁最常报告的抗胆碱能不良反应）。
