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Predicting transporter effects on the pharmacokinetics of metabolized drugs
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Resumo(s)
There is an ongoing debate among the scientific community regarding the role of uptake and efflux transporters in drug BA and BA predictions from in vitro systems. The studies presented in this thesis were planned to clarify whether a simple categorization of drugs (BDDCS) may allow prediction of the importance of intestinal transporters on the disposition of drugs. The bidirectional transport of the highly S and highly P drugs verapamil and diltiazem (Class 1 drugs) and the highly P and low S drug saquinavir (Class 2 drug) was investigated across Caco-2 and MDR1-overexpressing MDCK (MM) cells. All drugs behaved as P-gp substrates in MM cells, but diltiazem and verapamil Papp was P-gp independent in Caco-2 cells. It was concluded that the superior TEER values of MM cell line leads to increased sensitivity in identifying P-gp substrates, although the Caco-2 cells are more representative of the human intestine. We know of no consistent evidence that P-gp affects verapamil absorption in the intestine, although it proved to be a P-gp substrate in the brain and in certain cellular systems. Therefore we studied the role of P-gp on the absorption of verapamil in the rat intestine in comparison with the Class 2 drug atorvastatin . Both drugs showed to be P-gp substrates in the rat intestine. Transporter-CYp3a4 interplay was evaluated for verapamil but there were no statistically significant differences between Extraction ratios in the absence and presence of GG918. Incubation of verapamil and digoxin was studied in the presence and absence of several uptake transporters inhibitors: tetraethylammonium, quinidine, rifampicin and verapamil, in Caco-2 cells. Initial uptake rates exhibited a linear profile for verapamil and suggested saturation for digoxin. The present results support the BDDCS prediction that transporter effects can be relevant in intestinal absorption of Class 2 drugs but not of Class 1 drugs.
Descrição
Tese de doutoramento, Farmácia (Biofarmácia e Farmacocinética), Universidade de Lisboa, Faculdade de Farmácia, 2011
Palavras-chave
Teses de doutoramento - 2011