Riviere J E, Martin-Jimenez T, Sundlof S F, Craigmill A L
NCSU College of Veterinary Medicine, Raleigh 27606, USA.
J Vet Pharmacol Ther. 1997 Dec;20(6):453-63. doi: 10.1046/j.1365-2885.1997.00095.x.
The purpose of this study was to apply the method of allometric analysis to a study of the comparative disposition of veterinary drugs using the Food Animal Residue Avoidance Databank (FARAD) as a source of the comparative pharmacokinetic data. An initial filtration of the FARAD data was performed in order to exclude drugs for which no pharmacokinetic data were available, in at least four species the route of administration was other than intravenous, and the matrix was different from blood, plasma or serum. This process restricted the study to a total of 44 candidate drugs. The primary pharmacokinetic parameter selected for study was half-life (t1/2). As this parameter is a composite of clearance (Cl) and volume of distribution (Vd), it was considered to be the most robust for interspecies scaling. Volume of distribution at steady state (Vdss) and clearance showed weak allometric correlations with weight across species. The relationships between body weight and elimination half-life (51/2 beta) were determined for this selected group of drugs by using the empirically determined function Y = a Wb. The function Y represents the parameter of concern (half-life), a is a coefficient typical of every drug (intercept), W is the species average body weight, and b is the scaling exponent. A total of 11 drugs (tetracycline, oxytetracycline, chlortetracycline, erythromycin, diazepam, prednisolone, cephapirin, ampicillin, gentamicin, apramycin and carbenicillin) showed statistically significant correlations and consequently are excellent candidates for interspecies extrapolation of pharmacokinetic parameters (half-life) in species of relevance to veterinary medicine. The remaining 33 drugs were divided into two groups which showed various degrees of lack of correlation. Many of the drugs that showed no allometric correlation were low hepatic extraction drugs. However, some other drugs demonstrated equivocal results which could either be due to a true lack of allometric correlation, or be inconclusive due to the lack of quality data or excessive variability due to the multi-laboratory origin of the FARAD data. The results of this study show that interspecies scaling is applicable to certain veterinary drugs. The experimental determination of the coefficients of the allometric equation for relevant pharmacokinetic parameters (clearance and volume of distribution) could be an important tool in estimating dose in species where the drug has never been studied. This could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally 'well behaved.'
本研究的目的是将异速生长分析方法应用于兽药比较处置的研究，以食品动物残留避免数据库（FARAD）作为比较药代动力学数据的来源。对FARAD数据进行了初步筛选，以排除那些没有药代动力学数据的药物、至少四种给药途径不是静脉注射的药物以及基质不同于血液、血浆或血清的药物。这一过程将研究限制在总共44种候选药物上。选择用于研究的主要药代动力学参数是半衰期（t1/2）。由于该参数是清除率（Cl）和分布容积（Vd）的综合指标，因此被认为是种间尺度转换中最可靠的参数。稳态分布容积（Vdss）和清除率在不同物种间与体重呈现出较弱的异速生长相关性。通过使用经验确定的函数Y = aWb，确定了这组选定药物的体重与消除半衰期（51/2 beta）之间的关系。函数Y代表所关注的参数（半衰期），a是每种药物的典型系数（截距），W是物种平均体重，b是尺度指数。共有11种药物（四环素、土霉素、金霉素、红霉素、地西泮、泼尼松龙、头孢匹林、氨苄西林、庆大霉素、阿普拉霉素和羧苄青霉素）显示出统计学上的显著相关性，因此是兽药相关物种中药代动力学参数（半衰期）种间外推的优秀候选药物。其余33种药物分为两组，显示出不同程度的缺乏相关性。许多显示没有异速生长相关性的药物是低肝提取率药物。然而，其他一些药物的结果不明确，这可能是由于真正缺乏异速生长相关性，或者由于缺乏高质量数据或由于FARAD数据的多实验室来源导致的过度变异性而无法得出结论。本研究结果表明，种间尺度转换适用于某些兽药。相关药代动力学参数（清除率和分布容积）的异速生长方程系数的实验测定可能是估计从未研究过该药物的物种剂量的重要工具。对于实验上“表现良好”的药物，这在避免药物开发第一阶段的剂量滴定研究方面可能会产生重要影响。
