Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans

BACKGROUND AND AIMS: In humans gut wall metabolism can be quantitatively as important as hepatic drug metabolism in limiting the systemic exposure to drugs after oral administration. However, it has been proposed that the role of gut wall metabolism might be overemphasized, because high luminal drug concentrations would lead to a saturation of gut wall metabolism. Therefore we investigated the impact of concentration and rate of intraluminal drug delivery on absorption (Fabs) and gastrointestinal extraction (EGI) of a luminally administered cytochrome P450 (CYP) 3A4 substrate (verapamil) using a multilumen perfusion catheter in combination with a stable isotope technique. METHODS: Two 20-cm-long, adjacent jejunal segments were isolated with the multilumen perfusion catheter in 7 subjects. In this study 80 mg of unlabeled verapamil (d0-verapamil15 min) was infused into one segment over a 15-minute period, 80 mg of 3-fold deuterated verapamil (d3-verapamil240 min) was administered over a 240-minute period into the other segment, and simultaneously, 5 mg of 7-fold deuterated verapamil (d7-verapamil) was injected intravenously over a 15-minute period. RESULTS: The rate of intraluminal drug delivery had only a modest effect on bioavailability of the verapamil isotopes (after correction for Fabs) (F/Fabsd3-verapamil240 min versus d0-verapamil15 min, 0.24 0.10 versus 0.20 0.09; P < .05). Accordingly, the EGI value for d3-verapamil240 min was 0.50 0.18 compared with 0.59 0.14 for d0-verapamil15 min (P < .05). In vivo, EGI(d0-verapamil15 min) correlated strongly with EGI(d3-verapamil240 min) (r = 0.94, P < .005). Moreover, intrinsic clearance of CYP3A4-mediated verapamil metabolism in homogenates of simultaneously collected shed enterocytes correlated with in vivo EGI of d0-verapamil15 min/d3-verapamil240 min (r = 0.62, P = .03). CONCLUSIONS: Substantial gut wall metabolism of verapamil occurs in humans and can be predicted from ex vivo data by use of shed enterocytes. The different intraluminal concentrations and rates of intraluminal drug delivery did not lead to a pronounced saturation of intestinal drug metabolism.Hartmut Glaeser, Siegfried Drescher, Ute Hofmann, Georg Heinkele, Andrew A. Somogyi, Michel Eichelbaum and Martin F. From