Pharmacokinetics of Organic Cation Transporter 1 (OCT1) Substrates in Oct1/2 Knockout Mice and Species Difference in Hepatic OCT1-Mediated Uptake.
Drug Metab Dispos
; 48(2): 93-105, 2020 02.
Article
en En
| MEDLINE
| ID: mdl-31771949
ABSTRACT
Organic cation transporter 1 (OCT1) plays a role in hepatic uptake of drugs, affecting in vivo exposure, distinguished primarily through pharmacogenetics of the SLC22A1 gene. The role of OCT1 in vivo has not been confirmed, however, via drug-drug interactions that similarly affect exposure. In the current research, we used Oct1/2 knockout mice to assess the role of Oct1 in hepatic clearance and liver partitioning of clinical substrates and assess the model for predicting an effect of OCT1 function on pharmacokinetics in humans. Four OCT1 substrates (sumatriptan, fenoterol, ondansetron, and tropisetron) were administered to wild-type and knockout mice, and plasma, tissue, and urine were collected. Tissue transporter expression was evaluated using liquid chromatography-mass spectrometry. In vitro, uptake of all compounds in human and mouse hepatocytes and human OCT1- and OCT2-expressing cells was evaluated. The largest effect of knockout was on hepatic clearance and liver partitioning of sumatriptan (2- to 5-fold change), followed by fenoterol, whereas minimal changes in the pharmacokinetics of ondansetron and tropisetron were observed. This aligned with uptake in mouse hepatocytes, in which inhibition of uptake of sumatriptan and fenoterol into mouse hepatocytes by an OCT1 inhibitor was much greater compared with ondansetron and tropisetron. Conversely, inhibition of all four substrates was evident in human hepatocytes, in line with reported clinical pharmacogenetic data. These data confirm the role of Oct1 in the hepatic uptake of the four OCT1 substrates and elucidate species differences in OCT1-mediated hepatocyte uptake that should be considered when utilizing the model to predict effects in humans. SIGNIFICANCE STATEMENT Studies in carriers of SLC22A1 null variants indicate a role of organic cation transporter 1 (OCT1) in the hepatic uptake of therapeutic agents, although OCT1-mediated drug-drug interactions have not been reported. This work used Oct1/2 knockout mice to confirm the role of Oct1 in the hepatic clearance and liver partitioning in mice for OCT1 substrates with reported pharmacogenetic effects. Species differences observed in mouse and human hepatocyte uptake clarify limitations of the knockout model for predicting exposure changes in humans for some OCT1 substrates.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Hepatocitos
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Factor 1 de Transcripción de Unión a Octámeros
/
Transportador 2 de Cátion Orgánico
/
Hígado
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
/
Male
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2020
Tipo del documento:
Article