Binding processes determine the stereoselective intestinal and hepatic extraction of verapamil in vivo
2012 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, Vol. 9, no 11, 3034-3045 p.Article in journal (Other academic) Published
The aim of this study was to investigate the mechanisms that might explain the observed route-dependent stereoselective pharmacokinetics (PK) of R/S-verapamil (R/S-VER) following oral and intravenous (iv) administration, by using a novel pig-specific physiologically based pharmacokinetic (PBPK) model suitable for investigations of first-pass extraction in the gut (EG) and the liver (EH). The PBPK model consisted of eight tissue compartments and was designed to simultaneously model the plasma concentration–time (PCT) profiles from three sampling sites after intrajejunal (ij) or iv administration of VER. The PBPK model successfully described the observed PCT profiles and EH over time for R- and S-VER. Extensive tissue binding to gut mucosa, liver, and lungs was an important determinant of the observed PK data. The stereoselective PK of VER was explained by a combination of several processes, including enantioselective plasma protein binding, blood-to-plasma partition, and gut mucosa and liver tissue distribution. The absence of stereoselectivity after iv dosing indicates that the first-pass tissue binding effect is an important factor in determining the steroselective PK of R/S-VER after oral administration. Additionally a combination of extensive liver tissue binding and a metabolite inhibition mechanism explained the time-dependent EH for both R- and S-VER. An in vitro–in vivocorrelation of absorption needs to consider these processes because tissue binding may confound analysis of a drug’s biopharmaceutical properties when using classical deconvolution or convolution techniques. In conclusion, a combination of PK data from multiple plasma sampling sites and a PBPK modeling approach provided a mechanistic understanding of processes involved in the intestinal absorption and first-pass extraction ofR- and S-VER.
Place, publisher, year, edition, pages
2012. Vol. 9, no 11, 3034-3045 p.
verapamil, PBPK, hepatic extraction, gut wall extraction, first-pass metabolism
Research subject Biopharmaceutics
IdentifiersURN: urn:nbn:se:uu:diva-165509DOI: 10.1021/mp3000875ISI: 000313769200008OAI: oai:DiVA.org:uu-165509DiVA: diva2:474019