title: Amide hydrolysis of a novel chemical series of microsomal prostaglandin E synthase-1 inhibitors induces kidney toxicity in the rat.
abstract: A novel microsomal prostaglandin E synthase 1 (mPGES-1) inhibitor induced kidney injury at exposures representing less than 4 times the anticipated efficacious exposure in man during a 7-day toxicity study in rats. The findings consisted mainly of tubular lesions and the presence of crystalline material and increases in plasma urea and creatinine. In vitro and in vivo metabolic profiling generated a working hypothesis that a bis-sulfonamide metabolite (determined M1) formed by amide hydrolysis caused this toxicity. To test this hypothesis, rats were subjected to a 7-day study and were administered the suspected metabolite and two low-potency mPGES-1 inhibitor analogs, where amide hydrolysis was undetectable in rat hepatocyte experiments. The results suggested that compounds with a reduced propensity to undergo amide hydrolysis, thus having less ability to form M1, reduced the risk of inducing kidney toxicity. Rats treated with M1 alone showed no histopathologic change in the kidney, which was likely related to underexposure to M1. To circumvent rat kidney toxicity, we identified a potent mPGES-1 inhibitor with a low propensity for amide hydrolysis and superior rat pharmacokinetic properties. A subsequent 14-day rat toxicity study showed that this compound was associated with kidney toxicity at 42, but not 21, times the anticipated efficacious exposure in humans. In conclusion, by including metabolic profiling and exploratory rat toxicity studies, a new and active mPGES-1 inhibitor with improved margins to chemically induced kidney toxicity in rats has been identified.
authors.affiliation: Drug Metabolism and Pharmacokinetics, CNSP iMed Science, AstraZeneca R&D, Innovative Medicines, Södertälje, Sweden. Johan.Bylund@farmbio.uu.se
authors.forename: Johan
authors.initials: J
authors.lastname: Bylund
authors.forename: Anita
authors.initials: A
authors.lastname: Annas
authors.forename: Dennis
authors.initials: D
authors.lastname: Hellgren
authors.forename: Sivert
authors.initials: S
authors.lastname: Bjurström
authors.forename: Håkan
authors.initials: H
authors.lastname: Andersson
authors.forename: Alexander
authors.initials: A
authors.lastname: Svanhagen
mesh_terms: D000818:Animals; D001711:Biotransformation; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D055432:Metabolomics; D000071876:Prostaglandin-E Synthases; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000633:toxicity*; D018675:Toxicity Tests
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases