Wyska Elzbieta, Szymura-Oleksiak Joanna, Pekala Elzbieta, Obruśnik Anna
Department of Pharmacokinetics and Physical Pharmacy, Collegium Medicum, Jagiellonian University, 9 Medyczna Street, 30-688 Cracow, Poland.
J Pharm Pharmacol. 2007 Apr;59(4):495-501. doi: 10.1211/jpp.59.4.0003.
The aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(-)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis-Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration-time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis-Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration-time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans.
本研究的目的是建立己酮可可碱（PTX）及其代谢产物1的R(-)-对映体利索茶碱（LSF）的药代动力学模型，以确定影响这些化合物从肠道吸收的一些因素，并阐明其非线性药代动力学所涉及的机制。以两种不同剂量对雄性CD-1小鼠口服和静脉注射PTX和LSF后收集血清样本。此外，将所研究的两种化合物与药物转运体调节剂维拉帕米和细胞色素P450（CYP）3A4抑制剂酮康唑共同给药。药代动力学分析表明，具有米氏型吸收和消除的单室模型最能描述PTX的药代动力学，而LSF浓度-时间数据则很好地拟合了具有一级吸收和米氏型消除过程的双室模型。两种共同给药的化合物均显著降低了PTX从0至60分钟的浓度-时间曲线下面积，并增加了LSF该参数的值。本研究结果间接表明，药物跨肠细胞转运的饱和以及从中枢室的消除可能是PTX非线性药代动力学的原因，而对于LSF，药代动力学中的剂量依赖性仅与从中枢室的消除有关。与维拉帕米和酮康唑共同给药后，PTX和LSF浓度的观察变化似乎可能具有临床意义，尤其是在长期治疗后，然而需要进一步研究来评估这些相互作用在人体中的重要性。
