Millecam Joske, De Baere Siegrid, Croubels Siska, Devreese Mathias
Laboratory of Pharmacology and Toxicology, Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
Front Pharmacol. 2019 Jun 27;10:712. doi: 10.3389/fphar.2019.00712. eCollection 2019.
The juvenile conventional pig has been suggested as a preclinical animal model to evaluate pharmacokinetic (PK), pharmacodynamic (PD), and safety parameters in children. However, a lot of developmental changes in pig physiology still need to be unraveled. While the ontogeny of pig biotransformation enzymes is getting more attention in literature, the developmental changes have not yet been investigated. Therefore, the aim of the current study was to evaluate the biotransformation of ibuprofen (IBU) in conventional pigs aged 1 week, 4 weeks, 8 weeks, and 6-7 months after a single intravenous and oral administration of 5 mg/kg body weight (BW) of IBU, using a PK approach in a crossover design for each age group. An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to determine 2-hydroxyibuprofen (2OH-IBU), carboxyibuprofen (COOH-IBU), and ibuprofen glucuronide (IBU-GlcA) in pig plasma. All three metabolites could be quantified in plasma and the following PK parameters were determined: , , AUC, area under plasma concentration-time curve (AUC) ratio between parent drug and metabolite, and the absolute oral bioavailability of the parent drug IBU. The plasma concentrations of the metabolites were always lower than those of IBU. The bioavailability was high, indicating limited pre-systemic biotransformation. The AUC ratio of 2OH-IBU and COOH-IBU/IBU showed a significant increase at 4 weeks of age compared to the 1-week-old and 6- to 7-month-old pigs. Interestingly, the IBU-GlcA/IBU AUC ratio did not change with age. The present study demonstrated that the main metabolites of IBU in human are also present in growing pigs. The oxidative phase I metabolism of IBU in growing conventional pigs did change with age. In contrast, age did not seem to affect the glucuronidation capacity of IBU in conventional pigs, although more studies with other substrate drugs are needed to confirm this.
幼年普通猪已被提议作为一种临床前动物模型，用于评估儿童的药代动力学（PK）、药效动力学（PD）和安全性参数。然而，猪生理学中许多发育变化仍有待阐明。虽然猪生物转化酶的个体发生在文献中受到越来越多的关注，但发育变化尚未得到研究。因此，本研究的目的是在每个年龄组采用交叉设计的PK方法，评估1周龄、4周龄、8周龄和6至7月龄的普通猪在单次静脉注射和口服5mg/kg体重（BW）布洛芬（IBU）后的生物转化情况。开发并验证了一种超高效液相色谱-串联质谱（UPLC-MS/MS）方法，用于测定猪血浆中的2-羟基布洛芬（2OH-IBU）、羧基布洛芬（COOH-IBU）和布洛芬葡萄糖醛酸苷（IBU-GlcA）。所有三种代谢物均可在血浆中定量，并测定了以下PK参数： 、 、AUC、母体药物与代谢物之间的血浆浓度-时间曲线下面积（AUC）比值以及母体药物IBU的绝对口服生物利用度。代谢物的血浆浓度始终低于IBU。生物利用度较高，表明首过生物转化有限。与1周龄和6至7月龄的猪相比，2OH-IBU和COOH-IBU/IBU的AUC比值在4周龄时显著增加。有趣的是，IBU-GlcA/IBU的AUC比值并未随年龄变化。本研究表明，生长猪中也存在人类中IBU的主要代谢物。生长中的普通猪中IBU的氧化I相代谢确实随年龄变化。相比之下，年龄似乎并未影响普通猪中IBU的葡萄糖醛酸化能力，尽管需要更多使用其他底物药物的研究来证实这一点。
