RESUMO
Recently, protein-facilitated uptake has been suggested to be an important factor in the precise prediction of the pharmacokinetic (PK) profiles of drugs. In our previous study, a physiologically-based pharmacokinetic (PBPK) approach considering the mechanism of albumin-mediated hepatic uptake was developed for predicting human PK profiles. It was assumed that drugs affected by albumin-mediated hepatic uptake would bind only to albumin, which means that there would be over-estimation of the contribution of protein-facilitated uptake for a drug that could bind to multiple proteins. In this study, we developed a method that can evaluate the albumin binding fraction in plasma considering the affinity for other proteins. Based on the albumin binding fraction, the contribution of albumin-mediated hepatic uptake was theoretically estimated, and then the human PK profiles were predicted by our proposed PBPK approach incorporating this mechanism. As a result, the predicted human PK profiles agreed well with the observed ones, and the absolute average fold error of PK parameters was almost within a 1.5-fold error on average. These findings show the importance of considering protein-facilitated uptake and also suggest that our proposed PBPK approach can be useful in scientific discussions with regulatory authorities.
Assuntos
Modelos Biológicos , Preparações Farmacêuticas , Albuminas/metabolismo , Transporte Biológico , Humanos , Fígado/metabolismo , Preparações Farmacêuticas/metabolismo , FarmacocinéticaRESUMO
A variant in the breast cancer resistance protein (BCRP) gene, 421C> A is a useful biomarker for describing large inter-individual differences in the pharmacokinetics of sulfasalazine (SASP), a BCRP substrate. However, large intra-genotypic variability still exists in spite of the incorporation of this variant into the pharmacokinetics of SASP. Since miR-328 negatively regulates BCRP expression in human tissues, we hypothesized that exosomal miR-328 in plasma, which leaks from the intestines, is a possible biomarker for estimating BCRP activity in the human intestines. We established an immunoprecipitation-based quantitative method for circulating intestine-derived miR-328 in plasma using an anti-glycoprotein A33 antibody. A clinical study was conducted with an open-label, non-randomized, and single-arm design involving 33 healthy participants. Intestine-derived exosomal miR-328 levels positively correlated (P < 0.05) with SASP AUC0-48, suggesting that subjects with high miR-328 levels have low intestinal BCRP activity, resulting in the high AUC of SASP. Circulating intestine-derived exosomal miR-328 in plasma has potential as a possible biomarker for estimating BCRP function in the human intestines.