PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter-Individual Variability.
PBPK Model of Coproporphyrin I: Evaluation of the Impact of SLCO1B1 Genotype, Ethnicity, and Sex on its Inter-Individual Variability.
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DOI：
10.1002/psp4.12582
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Galetin A
中科院分区：
文献类型：
--
作者：
Takita H;Barnett S;Zhang Y;Ménochet K;Shen H;Ogungbenro K;Galetin A
共卟啉I(CPI)是OATP1B活性及其相关药物相互作用的内源性生物标志物。在这项研究中，建立了一个基于生理的最小药代动力学模型，以调查OATP1B1基因(C.521T>；C)、种族和性别对CPI药代动力学和基线个体变异性的影响。该模型实现了CPI肝血肝转运和肾排泄的机械化描述。通过将模型同时与三个独立的CPI临床数据(血浆和尿液数据)进行拟合，估计了关键的模型参数(例如，内源性CPI合成率和CPI肝脏摄取清除率)，这些数据来自白人(n=16，男性和女性)和亚裔印第安人(n=2.26，全部男性)受试者，这些受试者具有c.521个变体(TT、TC和CC)。优化的CPI模型成功地描述了以C.521T>；C基因型、种族和性别为协变量的观察数据。521CC的CPI肝脏活性比野生型低79%，亚裔印第安人比白人低42%，而男性的CPI合成比女性高23%。参数敏感性分析显示CPI合成位点假设(血液或肝脏)的边际影响，导致血浆和尿液CPI数据的可比性恢复。在521CC受试者中模拟了CPI-药物相互作用的较低幅度，这表明如果没有事先的OATP1B1基因分型，CPI-药物相互作用的风险被低估。CPI模型在其基线中纳入了影响个体间变异性的关键协变量，并强调了CPI建模的实用性，以促进前瞻性临床研究的设计，从而最大限度地提高该生物标记物的灵敏度。
Coproporphyrin I (CPI) is an endogenous biomarker of OATP1B activity and associated drug‐drug interactions. In this study, a minimal physiologically‐based pharmacokinetic model was developed to investigate the impact of OATP1B1 genotype (c.521T>C), ethnicity, and sex on CPI pharmacokinetics and interindividual variability in its baseline. The model implemented mechanistic descriptions of CPI hepatic transport between liver blood and liver tissue and renal excretion. Key model parameters (e.g., endogenous CPI synthesis rate, and CPI hepatic uptake clearance) were estimated by fitting the model simultaneously to three independent CPI clinical datasets (plasma and urine data) obtained from white (n = 16, men and women) and Asian‐Indian (n = 26, all men) subjects, with c.521 variants (TT, TC, and CC). The optimized CPI model successfully described the observed data using c.521T>C genotype, ethnicity, and sex as covariates. CPI hepatic active was 79% lower in 521CC relative to the wild type and 42% lower in Asian‐Indians relative to white subjects, whereas CPI synthesis was 23% higher in male relative to female subjects. Parameter sensitivity analysis showed marginal impact of the assumption of CPI synthesis site (blood or liver), resulting in comparable recovery of plasma and urine CPI data. Lower magnitude of CPI‐drug interaction was simulated in 521CC subjects, suggesting the risk of underestimation of CPI‐drug interaction without prior OATP1B1 genotyping. The CPI model incorporates key covariates contributing to interindividual variability in its baseline and highlights the utility of the CPI modeling to facilitate the design of prospective clinical studies to maximize the sensitivity of this biomarker.
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影响因子：
6.7
作者：
Guo Y;Chu X;Parrott NJ;Brouwer KLR;Hsu V;Nagar S;Matsson P;Sharma P;Snoeys J;Sugiyama Y;Tatosian D;Unadkat JD;Huang SM;Galetin A;International Transporter Consortium
通讯作者：
International Transporter Consortium
DOI：
10.1016/0020-711x(80)90195-0
发表时间：
1980-01-01
期刊：
INTERNATIONAL JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
KOSKELO, P;MUSTAJOKI, P
通讯作者：
MUSTAJOKI, P
影响因子：
2.1
作者：
Pasupula, Deepak Kumar;Reddy, P. S.
通讯作者：
Reddy, P. S.
影响因子：
3.7
作者：
Gertz, Michael;Tsamandouras, Nikolaos;Galetin, Aleksandra
通讯作者：
Galetin, Aleksandra
影响因子：
6.7
作者：
Barnett, Shelby;Ogungbenro, Kayode;Galetin, Aleksandra
通讯作者：
Galetin, Aleksandra