Plasma and urinary CP I and CP III concentrations in chimeric mice with human hepatocytes after rifampicin administration.

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pharmacology Research & Perspectives Pub Date : 2024-10-01 DOI:10.1002/prp2.70017
Yurina Shishido, Tomohiro Yoshida, Keiyu Oshida, Masashi Uchida
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Abstract

The interest in transporter-mediated drug interactions has been increasing in the field of drug development. In this study, we measured the plasma and urinary concentrations of coproporphyrin (CP) I and CP III as endogenous substrates for organic anion-transporting polypeptide (OATP) using chimeric mice with human hepatocytes (PXB mice) and examined the influence of an OATP inhibitor, rifampicin (RIF). CP I and CP III were actively taken up intracellularly, and RIF inhibited the uptake in a concentration-dependent manner for both CP I and CP III in human hepatocytes (PXB-cells). Single doses of RIF at 10 and 30 mg/kg were orally or intravenously administered to PXB mice and wild-type ICR mice. Plasma concentrations (AUC0-8h) of CP I increased in both mice. However, a marked increase in CP III was only observed in ICR mice, after intravenous administration of RIF at 30 mg/kg. The IC50 values of RIF for intracellular CP I/III uptake and the unbound plasma concentrations of RIF suggested that the increase in plasma CP I is associated with the exposure of RIF to OATPs. The 24-h cumulative urinary excretions of CP I and CP III increased in both mice, but more markedly in PXB mice. Thus, RIF increased the plasma and urinary concentrations of CP I and CP III in the mice, as reported in humans, and CP I may be a more sensitive biomarker of OATP-mediated drug interactions in PXB mice.

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人肝细胞嵌合小鼠服用利福平后血浆和尿液中的 CP I 和 CP III 浓度。
在药物开发领域,人们对转运体介导的药物相互作用的兴趣与日俱增。在这项研究中,我们利用具有人类肝细胞的嵌合小鼠(PXB 小鼠)测定了作为有机阴离子转运多肽(OATP)内源性底物的共卟啉(CP)Ⅰ和CPⅢ的血浆和尿液浓度,并考察了 OATP 抑制剂利福平(RIF)的影响。在人肝细胞(PXB-细胞)中,CP I 和 CP III 在细胞内被主动摄取,RIF 以浓度依赖的方式抑制了 CP I 和 CP III 的摄取。给 PXB 小鼠和野生型 ICR 小鼠口服或静脉注射单剂量 RIF(10 毫克/千克和 30 毫克/千克)。两种小鼠血浆中 CP I 的浓度(AUC0-8h)均有所增加。然而,只有在静脉注射 30 毫克/千克的 RIF 后,ICR 小鼠的 CP III 浓度才会显著增加。RIF 在细胞内摄取 CP I/III 的 IC50 值和 RIF 的非结合血浆浓度表明,血浆 CP I 的增加与 RIF 暴露于 OATPs 有关。两种小鼠 24 小时尿液中 CP I 和 CP III 的累积排泄量都有所增加,但 PXB 小鼠的情况更为明显。因此,RIF 增加了小鼠血浆和尿液中 CP I 和 CP III 的浓度,正如在人类身上所报道的那样,CP I 可能是 PXB 小鼠体内 OATP 介导的药物相互作用的更敏感的生物标志物。
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来源期刊
Pharmacology Research & Perspectives
Pharmacology Research & Perspectives Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics
CiteScore
5.30
自引率
3.80%
发文量
120
审稿时长
20 weeks
期刊介绍: PR&P is jointly published by the American Society for Pharmacology and Experimental Therapeutics (ASPET), the British Pharmacological Society (BPS), and Wiley. PR&P is a bi-monthly open access journal that publishes a range of article types, including: target validation (preclinical papers that show a hypothesis is incorrect or papers on drugs that have failed in early clinical development); drug discovery reviews (strategy, hypotheses, and data resulting in a successful therapeutic drug); frontiers in translational medicine (drug and target validation for an unmet therapeutic need); pharmacological hypotheses (reviews that are oriented to inform a novel hypothesis); and replication studies (work that refutes key findings [failed replication] and work that validates key findings). PR&P publishes papers submitted directly to the journal and those referred from the journals of ASPET and the BPS
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