Advancing Estimation of Hepatobiliary Clearances in Physiologically Based Pharmacokinetic Models of Rosuvastatin Using Human Hepatic Concentrations.
Pharm Res
; 38(12): 2035-2046, 2021 Dec.
Article
em En
| MEDLINE
| ID: mdl-34862570
ABSTRACT
PURPOSE:
To estimate hepatobiliary clearances of rosuvastatin via simultaneously fitting to reported human positron emission tomography (PET) data in the liver and gallbladder.METHODS:
A hepatobiliary model incorporating five intrinsic hepatobiliary clearances (active uptake clearance at the sinusoidal membrane, efflux clearance by passive diffusion through the sinusoidal membrane, influx clearance by passive diffusion through sinusoidal membrane, clearance of biliary excretion at the canalicular membrane, and intercompartment clearance from the intrahepatic bile duct to the gallbladder) and three compartments (liver, intrahepatic bile duct, and gallbladder) was developed to simultaneously fit rosuvastatin liver and gallbladder data from a representative subject reported by Billington et al. (1). Two liver blood supply input functions, arterial input function and dual input function (using peripheral venous as an alternative to portal vein), were assessed. Additionally, the predictive performance between the established model and four reported models trained with only systemic exposure data, was evaluated by comparing simulated liver and gallbladder profiles with observations.RESULTS:
The established hepatobiliary model well captured the kinetic profiles of rosuvastatin in the liver and gallbladder during the PET scans. Application of dual input function led to a marked underestimation of liver concentrations at the initial stage after i.v. dosing which cannot be offset by altering model parameter values. The simulated hepatobiliary profiles from three of the reported models demonstrated substantial deviation from the observed data.CONCLUSIONS:
The present study highlights the necessity of using hepatobiliary data to verify and improve the predictive performance of hepatic disposition of rosuvastatin.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Eliminação Hepatobiliar
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Rosuvastatina Cálcica
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Vesícula Biliar
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Fígado
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
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UNITED STATES OF AMERICA
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US
/
USA