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

AIM To determine the scaling factors required for inclusion of renal drug glucuronidation clearance in the prediction of total clearance via glucuronidation (CLUGT). METHODS 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) byMKMand paired cortical (KCM) andmedullary (KMM) microsomesweremeasured, alongwith 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. Datawere 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. RESULTS 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 in KCM than in KMM. The abundance of UGT1A9 in MKM (61.3 pmol mg(-1)) was 2.7 fold higher than that reported for HLM. CONCLUSIONS Scaled renal PRO glucuronidation CLint,u,UGT was double that of liver. Renal CLint,u,UGT should be accounted for in the IV-IVE of UGT1A9 and considered for UGT1A6 and 2B7 substrates. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Multiple drugs, non-drug xenobiotics and endobiotics are glucuronidated by human kidney. UDP-glucuronosyltransferase (UGT) 1A proteins and UGT2B7 are variably expressed in the tubule components of the human nephron. Development of kidney specific in vitro-in vivo extrapolation (IV-IVE) approaches is hampered by the limited availability of microsomal protein per gram of kidney (MPPGK) and knowledge of the content and anatomic distribution of individual UGT enzymes. WHAT THIS STUDY ADDS This study provides scaling factors to assess the relative contribution of the kidney to renal drug clearance via glucuronidation. It demonstrates anatomic differences in renal glucuronidation activity and provides data on the contents of UGT1A6, UGT1A9 and UGT2B7 in human kidney cortex and medulla. It establishes that UGT1A9 is 2.7-fold more abundant in human kidney microsomes than hepatic microsomes, indicating the need to include renal glucuronidation unbound intrinsic clearance in IV-IVE predictions for substrates glucuronidated by UGT1A9.