Scaling factors for the in vitro-in vivo extrapolation (IV-IVE) of renal drug and xenobiotic glucuronidation clearance

British Journal of Clinical Pharmacology
Kathleen M KnightsJohn O Miners

Abstract

To determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CLUGT ). Microsomal protein per gram of kidney (MPPGK) was determined for human 'mixed' kidney (n = 5) microsomes (MKM). The glucuronidation activities of deferiprone (DEF), propofol (PRO) and zidovudine (AZT) by MKM and paired cortical (KCM) and medullary (KMM) microsomes were measured, along with the UGT 1A6, 1A9 and 2B7 protein contents of each enzyme source. Unbound intrinsic clearances (CLint,u,UGT ) for PRO and morphine (MOR; 3- and 6-) glucuronidation by MKM, human liver microsomes (HLM) and recombinant UGT1A9 and 2B7 were additionally determined. Data were scaled using in vitro-in vivo extrapolation (IV-IVE) approaches to assess the influence of renal CLint,u,UGT on the prediction accuracy of the calculated CLUGT values of PRO and MOR. MPPGK was 9.3 ± 2.0 mg g(-1) (mean ± SD). The respective rates of DEF (UGT1A6), PRO (UGT1A9) and AZT (UGT2B7) glucuronidation by KCM were 1.4-, 5.2- and 10.5-fold higher than those for KMM. UGT 1A6, 1A9 and 2B7 were the only enzymes expressed in kidney. Consistent with the activity data, the abundance of each of these enzymes was greater...Continue Reading

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Citations

Apr 2, 2016·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Daniel ScotcherAleksandra Galetin
Aug 20, 2016·Journal of Clinical Pharmacology·James F BurrisMichael D Reed
Nov 10, 2018·The Journal of Pharmacology and Experimental Therapeutics·Aaron M TeitelbaumAllan E Rettie
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Mar 9, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Daniel ScotcherAleksandra Galetin
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May 6, 2020·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Yixuan LiChunze Zhang
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Jun 12, 2020·Chemical Research in Toxicology·Markus WallesPeter End
Sep 22, 2020·Molecular Pharmaceutics·Abdul BasitBhagwat Prasad

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