Quantitative Prediction of Intestinal Glucuronidation of Drugs in Rats Using In Vitro Metabolic Clearance Data
| Autor: | Katsuhiro Yamano, Toshio Teramura, Kazuhiro Tetsuka, Fumihiro Nakamori, Shigeyuki Terashita, Takako Furukawa, Yoichi Naritomi, Hiroyuki Moriguchi |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Metabolic Clearance Rate Drug Evaluation Preclinical Glucuronidation Pharmaceutical Science Pharmacology digestive system Rats Sprague-Dawley chemistry.chemical_compound Glucuronides Pharmacokinetics In vivo Oral administration Microsomes medicine Animals Pharmacology (medical) Glucuronosyltransferase Intestinal Mucosa Tolcapone Chemistry Rats Bioavailability Pharmaceutical Preparations Microsome Quercetin Forecasting medicine.drug |
| Zdroj: | Drug Metabolism and Pharmacokinetics. 27:171-180 |
| ISSN: | 1347-4367 |
| Popis: | UDP-glucuronosyltransferase (UGT) is highly expressed in the small intestine and catalyzes the glucuronidation of small molecules, which may affect the oral bioavailability of drugs. However, no method of predicting the in vivo observed fraction of absorbed drug (F(a)F(g)) affected by UGT has yet been established. Here, we investigated the relationship between F(a)F(g) and in vitro clearance of nine UGT substrates (ketoprofen, tolcapone, telmisartan, raloxifene, entacapone, resveratrol, buprenorphine, quercetin, and ezetimibe) via UGT in intestinal microsomes (CL(int, UGT)) in rats. F(a)F(g) was calculated from pharmacokinetic parameters after intravenous and oral administration or using the portal-systemic concentration difference method, with values ranging from 0.027 (ezetimibe) to 1 (tolcapone). Glucuronides of model compounds were observed in the portal plasma after oral administration, with CL(int, UGT) values ranging from 57.8 (tolcapone) to 19,200 µL/min/mg (resveratrol). An inverse correlation between F(a)F(g) and CL(int, UGT) was observed for most compounds and was described using a simplified intestinal availability model reported previously. This model gave accurate predictions of F(a)F(g) values for three in-house compounds. Our results show that F(a)F(g) in rats is affected by UGT and can be predicted using CL(int, UGT). This work should hasten the development of a method to predict F(a)F(g) in humans. |
| Databáze: | OpenAIRE |
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