Testicular distribution and toxicity of a novel LTA4H inhibitor in rats.
JNJ 40929837, a novel leukotriene A4 hydrolase inhibitor in drug development, was reported to induce testicular toxicity in rats. The mechanism of toxicity was considered to be rodent specific and not relevant to humans. To further investigate this finding in rats, the distribution and toxicokinetics of JNJ 40929837 and its two metabolites, M1 and M2, were investigated. A quantitative whole body autoradiography study showed preferential distribution and retention of JNJ 40929837-derived radioactivity in the testes consistent with the observed site of toxicity. Subsequent studies with unlabeled JNJ 40929837 showed different metabolite profiles between the plasma and testes. Following a single oral 50mg/kg dose of JNJ 40929837, M2 was the primary metabolite in plasma whereas M1 was the primary metabolite in testes. The exposure of M1 was 386-fold higher in the testes compared to plasma whereas M2 had limited exposure in testes. Furthermore, the Tmax of M1 was 48h in testes suggesting a large accumulation potential of this metabolite in testes compared to plasma. Following six months of repeated daily oral dosing, M1 accumulated approximately five-fold in the testes whereas the parent did not accumulate. These results indicate that the toxicokinetic profiles of JNJ 40929837 and its two metabolites in testes are markedly different compared to plasma and support the importance of understanding the toxicokinetic profiles of compounds and their metabolites in organs/tissues where toxicity is observed.
Discovery Sciences, Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA. Electronic address: pward4@its.jnj.com.
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Discovery Sciences, Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA.
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D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013737:Testis / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D014326:Tropanes / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051598:Whole Body Imaging
D004791:Enzyme Inhibitors; C000597450:JNJ-40929837; D013844:Thiazoles; D014326:Tropanes; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase
Distribution; Metabolite; Rat; Testes; Toxicity; Toxicokinetics