The effect of ketoconazole on the jejunal permeability and CYP3A metabolism of (R/S)‐verapamil in humans

Abstract

Aims The purpose of this human intestinal perfusion study was to investigate the effect of ketoconazole on the jejunal permeability and first‐pass metabolism of (R)‐ and (S)‐verapamil in humans. Methods A regional single‐pass perfusion of the jejunum was performed using a Loc‐I‐Gut® perfusion tube in six healthy volunteers. Each perfusion lasted for 200 min and was divided into two periods of 100 min each. The inlet concentration of (R/S)‐verapamil was 120 mg l−1 in both periods, and ketoconazole was added at 40 mg l−1 in period 2. (R/S)‐verapamil was also administered as a short intravenous infusion of 5 mg, over a period of 10 min. The appearance ratios of the CYP3A formed metabolites (R)‐ and (S)‐norverapamil were also estimated in the outlet jejunal perfusate. Results The effective jejunal permeability (Peff) of both (R)‐ and (S)‐verapamil was unaffected by the addition of ketoconazole in period 2 suggesting that ketoconazole had no effect on the P‐glycoprotein mediated efflux. However, the appearance ratio of both (R)‐ and (S)‐norverapamil in the outlet jejunal perfusate decreased in the presence of ketoconazole. The rate of absorption into plasma of (R)‐ and (S)‐verapamil increased despite the low dose of ketoconazole added, indicating an inhibition of the gut wall metabolism of (R/S)‐verapamil by ketoconazole. Conclusions Ketoconazole did not affect the jejunal Peff of (R/S)‐verapamil, but it did increase the overall transport into the systemic circulation (bioavailability), probably by inhibition of the gut wall metabolism of verapamil. This might be due to ketoconazole being less potent as an inhibitor of P‐glycoprotein than of CYP3A4 in vivo in humans.

Stereoselective First-Pass Metabolism of Verapamil in the Small Intestine and Liver in Rats

“…First-pass metabolism of VP in enterocytes has also been reported in humans (Sandström et al, 1999;von Richter et al, 2001). The extraction ratios of R-and S-VP by enterocytes were 0.49 and 0.68, respectively, and those by liver were 0.63 and 0.79, respectively (Sandström et al, 1999). These results indicate that S-VP undergoes extensive first-pass metabolism with the same direction of stereoselectivity in both organs.…”

“…administration of VP (80 mg/kg) to healthy volunteers (Hashiguchi et al, 1996), corrected for the B/P ratio (Robinson and Mehvar, 1996), were 29 and 121 ng ⅐ h/ml, respectively, and the corresponding AUCs of the NVP enantiomers were 80 and 168 ng ⅐ h/ml. First-pass metabolism of VP in enterocytes has also been reported in humans (Sandström et al, 1999;von Richter et al, 2001). The extraction ratios of R-and S-VP by enterocytes were 0.49 and 0.68, respectively, and those by liver were 0.63 and 0.79, respectively (Sandström et al, 1999).…”

Absorption/Metabolism of Sulforaphane and Quercetin, and Regulation of Phase Ii Enzymes, in Human Jejunum in Vivo

“…4) Are Caco-2 cells a good model for examination of transport, metabolism, and gene regulation for these compounds? To answer these questions, we have used the Loc-I-Gut system as a validated experimental setup to determine in vivo P eff -values (Lennernas et al, 1992;Lennernas, 1998), intestinal transport, and gut wall metabolism in vivo in humans (Sandstrom et al, 1999). The major advantage of the current perfusion method is that it is possible to measure absorption, metabolism, and secretion without influence of other gastrointestinal factors such as transit time and regional pHdifferences.…”

“…The concentrations of antipyrine in the perfusion solutions were analyzed by HPLC/UV using a previously validated method (Lindahl et al, 1996;Sandstrom et al, 1999). The total radioactivity of […”

Expression of paclitaxel-inactivating CYP3A activity in human colorectal cancer: implications for drug therapy

“…Evidences for the expression of CYP3A in extrahepatic tissues have been reported, and in particular the expression of CYP3A enzyme activity or immunoreactive protein in diverse segments of intestinal epithelium has been shown. This includes oesophageal squamous mucosa (Hughes et al, 1999), duodenum, gallbladder (Yokose et al, 1999) and jejunum (Sandstrom et al, 1999). The fact that intestinal CYP3A significantly contribute to the 'first pass' metabolism of several drugs (Kolars et al, 1991) indicates that local metabolism in intestinal epithelium is a relevant factor in individuals treated with CYP3A substrates.…”