Identification and characterization of oxymetazoline glucuronidation in human liver microsomes: Evidence for the involvement of UGT1A9.
Summary of "Identification and characterization of oxymetazoline glucuronidation in human liver microsomes: Evidence for the involvement of UGT1A9."
The incubation of oxymetazoline, a nonprescription nasal decongestant, with human liver microsomes (HLMs) supplemented with uridine-5-diphosphoglucuronic acid (UDPGA) generated glucuronide metabolite as observed by LC/MS/MS. The uridine glucuronosyltransferases (UGTs) responsible for the O-glucuronidation of oxymetazoline remain thus far unidentified. The glucuronide formed in HLMs was identified by LC/MS/MS and characterized by one- and two-dimensional NMR to be the beta-O-glucuronide of oxymetazoline. UGT screening with expressed UGTs identified UGT1A9 as the single UGT isoform catalyzing O-glucuronidation of oxymetazoline. Oxymetazoline O-glucuronidation by using HLMs was best fitted to the allosteric sigmoidal model. The derived S(50) and V(max) values were 2.42 +/- 0.40 mM and 8.69 +/- 0.58 pmole/(min mg of protein), respectively, and maximum clearance (CL(max)) was 3.61 L/min/mg. Oxymetazoline O-glucuronidation by using expressed UGT1A9 was best fitted to the substrate inhibition model. The derived K(m) and V(max) values were 2.53 +/- 1.03 mM and 54.18 +/- 16.92 pmole/(min mg of protein), respectively, and intrinsic clearance (CL(int)) was 21.41 L/(min mg). Our studies indicate that oxymetazoline is not glucuronidated at its nanomolar intranasal dose and thus is eliminated unchanged, because UGT1A9 would only contribute to its elimination at the toxic plasma concentrations. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci
XX:
1-10, 2010.
Affiliation
Drug Metabolism and Pharmacokinetics, Immunoinflammation Centre of Excellence in Drug Discovery, GlaxoSmithKline, Collegeville, Pennsylvania.
Journal Details
This article was published in the following journal.
Name: Journal of pharmaceutical sciences
ISSN: 1520-6017
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20669329
- DOI: http://dx.doi.org/10.1002/jps.22303
Medical and Biotech [MESH] Definitions
Microsomes, Liver
Closed vesicles of fragmented endoplasmic reticulum created when liver cells or tissue are disrupted by homogenization. They may be smooth or rough.
Oxidoreductases, O-demethylating
Drug metabolizing enzymes which oxidize methyl ethers. Usually found in liver microsomes.
Ampyrone
A metabolite of AMINOPYRINE with analgesic and anti-inflammatory properties. It is used as a reagent for biochemical reactions producing peroxides or phenols. Ampyrone stimulates LIVER MICROSOMES and is also used to measure extracellular water.
Genes, Mos
Retrovirus-associated DNA sequences (mos) originally isolated from the Moloney murine sarcoma virus (Mo-MSV). The proto-oncogene mos (c-mos) codes for a protein which is a member of the serine kinase family. There is no evidence as yet that human c-mos can become transformed or has a role in human cancer. However, in mice, activation can occur when the retrovirus-like intracisternal A-particle inserts itself near the c-mos sequence. The human c-mos gene is located at 8q22 on the long arm of chromosome 8.
Liver Transplantation
The transference of a part of or an entire liver from one human or animal to another.
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