Human Pharmacokinetic Prediction of UDP-Glucuronosyltransferase Substrates with an Animal Scale-Up Approach

Abstract

ABSTRACT:The aim of the current study was to evaluate the accuracy of allometric scaling methods for drugs metabolized by UDP-glucuronosyltransferases (UGTs), such as ketoprofen, imipramine, lorazepam, levofloxacin, zidovudine, diclofenac, furosemide, raloxifene, gemfibrozil, mycophenolic acid, indomethacin, and telmisartan. Human plasma clearance (CL) predictions were conducted from preclinical in vivo data by using multiple-species allometry with the rule of exponents and single-species allometric scaling (SSS) of mice, rats, monkeys, or dogs. Distribution volume at a steady state (V ss ) was predicted by multiple-species allometry or SSS of V ss . Oral plasma clearance (CL po ) was calculated under the assumption that F a ؋ F g was equivalent across species. Each of the results was compared with the observed parameter calculated from the clinical data after intravenous or oral administration. Multiple-species allometry and SSS of mice, rats, and dogs resulted in a similar accuracy of CL and CL po predictions. Monkeys tended to provide the most accurate predictions of human CL and CL po . The ability to predict the half-life, which was determined from CL and V ss predictions, was more accurate in SSS of rats and monkeys. The in vivo fraction metabolized by glucuronidation (f m,UGT ) in bile duct-cannulated monkeys was relatively similar to that of humans compared with other animal species, which likely contributed to the highest accuracy of SSS prediction of monkeys. On the basis of the current results, monkeys would be more reliable than other animal species in predicting human pharmacokinetics and f m,UGT for drugs metabolized by UGTs.

Evaluation and Optimization of Blood Micro-Sampling Methods: Serial Sampling in a Cross-Over Design from an Individual Mouse

“…However, where comparisons were possible, the mouse PK for the compounds used in our studies were comparable to the literature. For example, gemfibrozil PK study in mouse reported a bioavailability of 73% which was similar to the 60% that we report in our studies (36) .…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…The very minor component being metabolized is represented by a pharmacologically inactive acyl glucuronide, which is the only metabolite that has been identified in human plasma and urine and accounts for approximately 11% of total radioactivity in plasma. Formation of the glucuronide metabolite in humans can best be predicted preclinically using canine data (Deguchi et al, 2011). The P450 enzymes are not involved in the metabolism of telmisartan, and an inhibition of CYP2C9 function has only been observed at very high and probably supratherapeutic concentrations .…”

Impact of Intestinal Glucuronidation on the Pharmacokinetics of Raloxifene

“…UGT1A8 and UGT1A10, isozymes that are absent in the human liver, are thought to glucuronidate raloxifene mainly in the intestine and lead to extremely low F (Kemp et al, 2002;Jeong et al, 2005). F of raloxifene in rats and dogs was originally reported as 39 and 17%, respec-tively (Lindstrom et al, 1984), and have been recently reported as 4 and 0%, respectively (Deguchi et al, 2011). The UGT isozymes responsible for the glucuronidation of raloxifene and its intestinal and hepatic availabilities (Fg and Fh, respectively) in preclinical animals have not been investigated adequately.…”