Farah Aida A Zairol Azwan, Nor Asyikin Mohd Tahir, Shamin Mohd Saffian, Mohd Makmor-Bakry, Mohd Shahrir Mohamed Said
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引用次数: 0
Abstract
Introduction: Allopurinol and its active metabolite, oxypurinol, reduce uric acid concentrations through xanthine oxidase inhibition by suppressing the conversion of hypoxanthine and xanthine. Oxypurinol plays a prominent role in allopurinol's pharmacological activity due to its longer elimination half-life. Despite decades of clinical use, establishing an optimal dosing strategy to consistently achieve the target serum uric acid concentration lower than 0.36 mmol L-1 remains challenging. This review aimed to summarize the development of population pharmacokinetic modeling for oxypurinol and analyze factors influencing its pharmacokinetic variability.
Methods: PubMed, Web of Science, and Scopus were systematically searched from database inception until January 2025, adhering to the PRISMA guideline. Studies were eligible if they involved oxypurinol population pharmacokinetic analyses in adults receiving allopurinol and employed nonlinear mixed-effects modeling.
Results: Eight studies met the inclusion criteria, mostly involving adult gout patients. Pharmacokinetic analyses of oxypurinol employed a one-compartment model, incorporating firstorder absorption and elimination, reporting clearance value of 0.60-1.74 L h-1 and volume of distribution 38.1-59.3 L. Covariates associated with oxypurinol clearance included creatinine clearance, body weight, normal fat mass, fat-free mass, ethnicity, genetic polymorphisms, and concomitant diuretics; whereas, total body weight was found as significant predictors for volume of distribution.
Discussions: Reported values for oxypurinol clearance and volume of distribution varied across studies. The small sample sizes and underrepresentation of certain populations, particularly Asians, restrict the generalizability of these findings.
Conclusion: Further research involving larger, more diverse cohorts is needed to refine therapeutic drug monitoring and identify potential covariates across different populations to optimize allopurinol therapy.
别嘌呤醇及其活性代谢物氧嘌呤醇通过抑制次黄嘌呤和黄嘌呤的转化来抑制黄嘌呤氧化酶，从而降低尿酸浓度。氧嘌呤醇由于其较长的消除半衰期，在别嘌呤醇的药理活性中起着突出的作用。尽管数十年的临床应用，建立一个最佳的给药策略，以持续实现低于0.36 mmol L-1的目标血清尿酸浓度仍然具有挑战性。本文综述了氧嘌呤醇群体药代动力学模型的研究进展，并对影响其药代动力学变异性的因素进行了分析。方法：遵循PRISMA指南，系统检索PubMed、Web of Science和Scopus从数据库建立到2025年1月。如果研究涉及到接受别嘌呤醇治疗的成人的氧嘌呤醇群体药代动力学分析，并采用非线性混合效应模型，则该研究是合格的。结果：8项研究符合纳入标准，主要涉及成年痛风患者。氧尿醇的药代动力学分析采用单室模型，纳入了首先吸收和消除，报告清除率为0.60-1.74 L h-1，分布体积为38.1-59.3 L。与氧尿醇清除率相关的协变量包括肌酐清除率、体重、正常脂肪量、无脂肪量、种族、遗传多态性和伴随利尿剂；然而，总体重被发现是体积分布的显著预测因子。讨论：报告的氧嘌呤醇清除率和分布量在不同的研究中有所不同。样本量小，某些人群代表性不足，特别是亚洲人，限制了这些发现的普遍性。结论：需要进一步的研究，包括更大、更多样化的队列，以完善治疗药物监测，并确定不同人群的潜在协变量，以优化别嘌呤醇治疗。
期刊介绍：
Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism.
More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.
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