Quantitative prediction of human intestinal glucuronidation effects on intestinal availability of UDP-glucuronosyltransferase substrates using in vitro data.
We investigated whether the effects of intestinal glucuronidation on the first-pass effect can be predicted from in vitro data for UDP-glucuronosyltransferase (UGT) substrates. Human in vitro intrinsic glucuronidation clearance (CL(int, UGT)) for 11 UGT substrates was evaluated using pooled intestinal microsomes (4.00-4620 μl · min⁻¹ · mg⁻¹) and corrected by the free fraction in the microsomal mixture (CLu(int), (UGT) = 5.2-5133 μl · min⁻¹ · mg⁻¹). Eleven UGT substrates were stable against intestinal cytochrome P450, indicating intestinal glucuronidation has a main effect on human intestinal availability. Oral absorbability intestinal availability (F(a)F(g)) values were calculated from in vivo pharmacokinetic parameters in the literature (F(a)F(g) = 0.01-1.0). It was found that CLu(int, UGT) and human F(a)F(g) have an inverse relationship that can be fitted to a simplified intestinal availability model. Experiments using Supersomes from insect cells expressing UGT isoforms showed that the substrates used were conjugated by various UGT isoforms. These results suggest that combining the simplified intestinal availability model and in vitro conjugation assay make it possible to predict human F(a)F(g) regardless of UGT isoform.
Astellas Pharma, Inc., Analysis and Pharmacokinetics Research Laboratories, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. fumihiro.nakamori@astellas.com
Fumihiro
F
Nakamori
Yoichi
Y
Naritomi
Ken-Ichi
K
Hosoya
Hiroyuki
H
Moriguchi
Kazuhiro
K
Tetsuka
Takako
T
Furukawa
Keitaro
K
Kadono
Katsuhiro
K
Yamano
Shigeyuki
S
Terashita
Toshio
T
Teramura
D000284:Administration, Oral; D001711:Biotransformation; D002463:Cell Membrane Permeability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020719:Glucuronides / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D007408:Intestinal Absorption; D007422:Intestines / Q000201:enzymology*; D007527:Isoenzymes; D007700:Kinetics; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000201:enzymology; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D020719:Glucuronides; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase