In vitro-in vivo correlation and translation to the clinical outcome for CJ-13,610, a novel inhibitor of 5-lipoxygenase.
The metabolism of the 5-lipoxygenase inhibitor, 4-(3-(4-(2-methyl-1H-imidazol-1-yl)phenylthio)phenyl)-tetrahydro-2H-pyran-4-carboxamide (CJ-13,610), was investigated in liver microsomes from human and preclinical species in an effort to compare metabolite profiles and evaluate the in vitro-in vivo correlation for metabolic clearance. Overall, the metabolite profile of CJ-13,610 was comparable across the species tested with multiple oxidative metabolites observed, including sulfoxidation. The sulfoxidation kinetics characterized in rat, dog, and human liver microsomes (HLM) indicated a low apparent Michaelis-Menten constant (K(m, app)) of 4 to 5 microM. Results from cDNA-expressed cytochrome P450 (P450) studies indicated that the metabolism in HLM was primarily mediated by CYP3A4 and 3A5. A subsequent in vitro study using ketoconazole as an inhibitor of CJ-13,610 sulfoxidation corroborated the CYP3A4/5-mediated pathway (IC(50) = 7 nM). Assessment of multiple methods for predicting the human pharmacokinetic profile observed with CJ-13,610 after a 30-mg single oral dose indicated that clearance scaled from human liver microsomes yielded a better prediction when coupled with a Vd(ss) term that was scaled from dog [area under the concentration-time curve (AUC) and half-life within 1.3-fold of actual] versus a Vd(ss) term obtained from rat. Single-species allometric scaling of clearance and Vd(ss) from dog pharmacokinetic studies was equally predictive, whereas scaling from rat resulted in underpredictions of both AUC and maximal concentration (C(max)). Results from these studies support the strategy of predicting human pharmacokinetics using human liver microsomal intrinsic clearance data. More importantly, results from the present investigation enabled the selection of alternative drug candidates from the chemical series via in vitro screening, while subsequently eliminating costly routine preclinical in vivo studies.
Matthew Hutzler
J
J
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, St. Louis Laboratories, St. Louis, Missouri, USA. matt.hutzler@boehringer-ingelheim.com
Linder
Collette D
CD
Melton
Roger J
RJ
Vincent
John
J
Daniels
J Scott
JS
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007700:Kinetics; D016859:Lipoxygenase Inhibitors; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D013440:Sulfides / Q000493:pharmacokinetics*
C496810:CJ 13610; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D013440:Sulfides