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Impact of concentration and rate of intraluminal drug delivery on absorption and gut wall metabolism of verapamil in humans
Author(s) -
Glaeser Hartmut,
Drescher Siegfried,
Hofmann Ute,
Heinkele Georg,
Somogyi Andrew A.,
Eichelbaum Michel,
Fromm Martin F.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.04.013
Subject(s) - verapamil , bioavailability , perfusion , pharmacology , drug metabolism , metabolism , pharmacokinetics , jejunum , chemistry , in vivo , drug , small intestine , gastrointestinal tract , absorption (acoustics) , medicine , endocrinology , biology , calcium , materials science , microbiology and biotechnology , composite material
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 (F abs ) and gastrointestinal extraction (E GI ) 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 (d 0 ‐verapamil 15 min ) was infused into one segment over a 15‐minute period, 80 mg of 3‐fold deuterated verapamil (d 3 ‐verapamil 240 min ) was administered over a 240‐minute period into the other segment, and simultaneously, 5 mg of 7‐fold deuterated verapamil (d 7 ‐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 F abs ) (F/F abs d 3 ‐verapamil 240 min versus d 0 ‐verapamil 15 min , 0.24 ± 0.10 versus 0.20 ± 0.09; P < .05). Accordingly, the E GI value for d 3 ‐verapamil 240 min was 0.50 ± 0.18 compared with 0.59 ± 0.14 for d 0 ‐verapamil 15 min ( P < .05). In vivo, E GI (d 0 ‐verapamil 15 min ) correlated strongly with E GI (d 3 ‐verapamil 240 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 E GI of d 0 ‐verapamil 15 min /d 3 ‐verapamil 240 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. Clinical Pharmacology & Therapeutics (2004) 76 , 230–238; doi: 10.1016/j.clpt.2004.04.013