Method for predicting human intestinal first-pass metabolism of UGT substrate compounds

• Published in: Xenobiotica Vol. 42; no. 10; pp. 980 - 988
• Main Authors: Furukawa, Takako, Yamano, Katsuhiro, Naritomi, Yoichi, Tanaka, Kohichiro, Terashita, Shigeyuki, Teramura, Toshio
• Format: Journal Article
• Language: English
• Published: England Informa Healthcare 01.10.2012; Taylor & Francis
• Subjects: Administration, Intravenous; Administration, Oral; Animals; Biochemistry - methods; Dogs; Glucuronides - administration & dosage; Glucuronides - chemistry; Glucuronides - metabolism; Glucuronides - pharmacokinetics; Glucuronosyltransferase - metabolism; Haplorhini; Humans; in vitro-in vivo correlation; Intestinal metabolism; Intestines - metabolism; Isoenzymes - metabolism; Male; Membranes, Artificial; Metabolome; Microsomes - metabolism; Permeability; Rats; Rats, Sprague-Dawley; Recombinant Proteins - metabolism; Reference Standards; Substrate Specificity; UDP-glucuronosyltransferase (UGT)
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2012.680620

As intestinal glucuronidation has been suggested to generate the low oral bioavailability (F) of drugs, estimating its effects would be valuable for selecting drug candidates. Here, we investigated the absorption and intestinal availability (FaFg) in animals, and intrinsic clearance via UDP-glucuronosyltransferase (UGT) in intestinal microsomes (CLint,UGT) for three drug candidates possessing a carboxylic acid group, in an attempt to estimate the impact of intestinal glucuronidation on F and select potential drug candidates with high F in humans. The FaFg values of the three test compounds were low in rats and monkeys (0.16-0.51), and high in dogs (≥0.81). Correspondingly, the CLint,UGT values were high in rats and monkeys (101-731 µL/min/mg), and low in dogs (≤ 59.6 µL/min/mg). A good inverse correlation was observed between FaFg and CLint,UGT, suggesting that intestinal glucuronidation was a major factor influencing FaFg of these compounds. By applying this correlation to FaFg in humans using human CLint,UGT values (26.9-114 µL/min/mg), compounds 1-3 were predicted to have relatively high FaFg. Our approach is expected to be useful for estimating the impact of intestinal glucuronidation on F in animals and semiquantitatively predicting human F for drug candidates.