Amide hydrolysis of a novel chemical series of microsomal prostaglandin e synthase-1 inhibitors induces kidney toxicity in the rat

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Fältnamn	Indikatorer	Metadata
000		03333naa a2200349 4500
001		oai:DiVA.org:uu-196595
003		SwePub
008		130311s2013 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1965952 URI
024	7	a https://doi.org/10.1124/dmd.112.0489832 DOI
040		a (SwePub)uu
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Bylund, Johan,d 1970-u Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Biokemisk farmakologi4 aut0 (Swepub:uu)johanbl
245	1 0	a Amide hydrolysis of a novel chemical series of microsomal prostaglandin e synthase-1 inhibitors induces kidney toxicity in the rat
264		c 2013-01-02
264	1	b American Society for Pharmacology & Experimental Therapeutics (ASPET),c 2013
338		a print2 rdacarrier
520		a 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.
650	7	a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmakologi och toxikologi0 (SwePub)301022 hsv//swe
650	7	a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmacology and Toxicology0 (SwePub)301022 hsv//eng
700	1	a Annas, Anita4 aut
700	1	a Hellgren, Dennis4 aut
700	1	a Bjurström, Sivert4 aut
700	1	a Andersson, Håkan4 aut
700	1	a Svanhagen, Alexander4 aut
710	2	a Uppsala universitetb Institutionen för farmaceutisk biovetenskap4 org
773	0	t Drug Metabolism And Dispositiond : American Society for Pharmacology & Experimental Therapeutics (ASPET)g 41:3, s. 634-641q 41:3<634-641x 0090-9556x 1521-009X
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-196595
856	4 8	u https://doi.org/10.1124/dmd.112.048983

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Av författaren/redakt...: Bylund, Johan, 1 ...; Annas, Anita; Hellgren, Dennis; Bjurström, Siver ...; Andersson, Håkan; Svanhagen, Alexa ...

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