albumin - publications

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1. Drug Metab Dispos. 2012 Jan 24. [Epub ahead of print]

Characterization of In Vitro Glucuronidation Clearance of a Range of Drugs in
Human Kidney Microsomes: Comparison to Liver and Intestinal Glucuronidation and
Impact of Albumin.

Gill KL, Houston JB, Galetin A.

University of Manchester.

Previous studies have shown the importance of the addition of albumin for
characterization of hepatic glucuronidation in vitro; however, no reports exist
on the effects of albumin on renal or intestinal microsomal glucuronidation
assays. This study characterized glucuronidation clearance (CL(int,UGT)) in human
kidney, liver and intestinal microsomes in the presence and absence of BSA for
seven drugs with a range of UGT1A9 and 2B7 specificity, namely diclofenac,
ezetimibe, gemfibrozil, mycophenolic acid, naloxone, propofol and telmisartan.
The impact of renal CL(int,UGT) on accuracy of vitro-in vivo extrapolation
(IVIVE) of glucuronidation clearance was investigated. Inclusion of 1% BSA for
acidic drugs and 2% for neutrals/bases in incubations was found to be suitable
for characterization of CL(int,UGT) in different tissues. Although BSA increased
CL(int,UGT) in all tissues, the extent was tissue- and drug-dependant. Scaled
CL(int,UGT) in the presence of BSA ranged from 2.22 to 207, 0.439 to 24.4, and
0.292 to 23.8 mL/min/g tissue in liver, kidney and intestinal microsomes. Renal
CL(int,UGT) (per g tissue) was up to 2-fold higher in comparison to liver for
UGT1A9 substrates; in contrast, CL(int,UGT) for UGT2B7 substrates represented
approximately 1/3 of hepatic estimates. Scaled renal CL(int,UGT) (in the presence
of BSA) was up to 30-fold higher than intestinal glucuronidation for the drugs
investigated. Use of in vitro data obtained in the presence of BSA and inclusion
of renal clearance improved the IVIVE of glucuronidation clearance, with 50%
drugs predicted within 2-fold of observed values. Characterization and
consideration of kidney CL(int,UGT) is particularly important for UGT1A9
substrates.

PMID: 22275465 [PubMed - as supplied by publisher]