Hajda Jacek Piotr, Jähnchen Eberhard, Oie Svein, Trenk Dietmar
Department of Clinical Pharmacology, Herz-Zentrum Bad Krozingen, Germany.
J Clin Pharmacol. 2002 Nov;42(11):1257-61. doi: 10.1177/009127002762491352.
The disposition of nortildine, the active metabolite of the synthetic opioid drug tilidine, was investigated in healthy volunteers in a randomized, single-dose, three-way crossover design. Three different treatments were administered: tilidine 50 mg intravenously, tilidine 50 mg orally, and nortilidine 10 mg intravenously. The plasma concentrations of tilidine, nortilidine, and bisnortilidine were determined and subjected to pharmacokinetic analysis using noncompartmental methods. The systemic bioavailability of tilidine was low (7.6% +/- 5.3%) due to a pronounced first-pass metabolism. The areas under the plasma concentration versus time curves (A UC) of nortilidine were similar following either oral or intravenous administration of tilidine 50 mg (375 +/- 184 vs. 364 +/- 124 ng.h.ml(-1)). AUC of nortilidine was 229 +/- 42 ng.h.ml(-1) after IV infusion of nortilidine 10 mg and thus much greater than after IV tilidine corrected for differences in dose. Nortilidine had a much lower volume of distribution (275 +/- 79 vs. 1326 +/- 477 L) and a somewhat lower clearance (749 +/- 119 vs. 1198 +/- 228 ml/min) than tilidine. About two-thirds of the dose of tilidine was metabolized to nortilidine, although only half of the latter fraction was available in the peripheral circulation. Nortilidine was subsequently metabolized to bisnortilidine. The mean ratio of the AUC of bisnortilidine to nortilidine was 0.65 +/- 0.14 following IV administration of nortilidine but 1.69 +/- 0.38 and 1.40 +/- 0.27 following oral and intravenous administration of tilidine, respectively. The shapes of the plasma concentration-time curves of the metabolites and parent drug declined in parallel, indicating that the disposition of the metabolites is formation rate limited. Thus, although two-thirds of the dose of tilidine is metabolized to nortilidine, only one-third of the dose is available systemically as nortilidine for interaction with the opiate receptors after both intravenous and oral dosing of tilidine. The remaining part of nortilidine is retained in the liver and is subsequently metabolized to bisnortilidine and yet unknown compounds.
在一项随机、单剂量、三交叉设计的研究中，对健康志愿者体内合成阿片类药物替利定的活性代谢产物去甲替利定的处置情况进行了研究。给予三种不同的治疗：静脉注射替利定50毫克、口服替利定50毫克和静脉注射去甲替利定10毫克。测定了替利定、去甲替利定和双去甲替利定的血浆浓度，并使用非房室方法进行药代动力学分析。由于明显的首过代谢，替利定的全身生物利用度较低（7.6%±5.3%）。口服或静脉注射50毫克替利定后，去甲替利定的血浆浓度-时间曲线下面积（AUC）相似（375±184对364±124纳克·小时·毫升⁻¹）。静脉输注10毫克去甲替利定后，去甲替利定的AUC为229±42纳克·小时·毫升⁻¹，因此远高于静脉注射替利定并校正剂量差异后的数值。与替利定相比，去甲替利定的分布容积低得多（275±79对1326±477升），清除率也略低（749±119对1198±228毫升/分钟）。约三分之二的替利定剂量代谢为去甲替利定，尽管后者只有一半可在外周循环中获得。去甲替利定随后代谢为双去甲替利定。静脉注射去甲替利定后，双去甲替利定与去甲替利定的AUC平均比值为0.65±0.14，而口服和静脉注射替利定后分别为1.69±0.38和1.40±0.27。代谢产物和母体药物的血浆浓度-时间曲线形状平行下降，表明代谢产物的处置受形成速率限制。因此，尽管三分之二的替利定剂量代谢为去甲替利定，但在静脉注射和口服替利定后，只有三分之一的剂量以去甲替利定的形式全身可用，用于与阿片受体相互作用。去甲替利定的其余部分保留在肝脏中，随后代谢为双去甲替利定和其他未知化合物。
