Association of UDP-glucuronosyltransferase 1A9 polymorphisms with adverse reactions to catechol-O-methyltransferase inhibitors in Parkinson's disease patients.

Abstract

PURPOSE:

To investigate the association between adverse reactions to catechol-O-methyltransferase (COMT) inhibitors and the UDP-glucuronosyltransferase 1A9 genotypes UGT1A9*1b and UGT1A9*3a, which were previously identified in individual cases of COMT inhibitor-induced toxicity.

METHODS:

The study included 52 Parkinson's disease (PD) patients on COMT inhibitors without evidence of adverse reactions and 11 PD patients who had been withdrawn from COMT inhibitors due to adverse reactions. UGT1A9*1b was identified by direct sequencing of the PCR amplification of the gene and UGT1A9*3a was assayed by real-time PCR.

RESULTS:

The frequency of the *3a/*3a and *1/*3a genotype variants was 45.5 % in subjects with adverse reactions and 21.1 % in subjects without adverse reactions [overall UGT1A9*3a allele frequency 27.3 vs. 11.5 %, P = 0.087; odds ratio (OR) 2.87, 95 % confidence interval (CI) 0.94-8.77]. The frequency of genotype combinations leading to low glucuronosyltransferase activity (*3a/*3a irrespective of *1b or *1/*3a and *1/*1b) was 5.8 % in subjects without adverse reactions and 36.4 % in subjects with adverse reactions (P = 0.014; OR 9.33, 95 % CI 1.71-50.78).

CONCLUSIONS:

In PD patients UDP-glucuronosyltransferase 1A9 genotypes are associated with adverse reactions to COMT inhibitors, leading to treatment withdrawal. UDP-glucuronosyltransferase 1A9 genotyping may be a screening and/or diagnostic test to assist individualized treatments with COMT inhibitors.

• Authors: Marco Ferrari, Emilia Martignoni, Fabio Blandini, Giulio Riboldazzi, Giorgio Bono, Franca Marino, Marco Cosentino
• Journal: European journal of clinical pharmacology (Eur J Clin Pharmacol) Vol. 68 Issue 11 Pg. 1493-9 (Nov 2012) ISSN: 1432-1041 [Electronic] Germany
• PMID: 22527346 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Antiparkinson Agents
• Catechol O-Methyltransferase Inhibitors
• Enzyme Inhibitors
• UGT1A9 protein, human
• Glucuronosyltransferase
• UDP-Glucuronosyltransferase 1A9

Topics

• Aged
• Aged, 80 and over
• Alleles
• Antiparkinson Agents (adverse effects, therapeutic use)
• Catechol O-Methyltransferase Inhibitors
• Cohort Studies
• Down-Regulation
• Enzyme Inhibitors (adverse effects, therapeutic use)
• Female
• Gene Frequency
• Genetic Association Studies
• Glucuronosyltransferase (genetics, metabolism)
• Hospitals, University
• Humans
• Italy
• Male
• Parkinson Disease (drug therapy, genetics, metabolism)
• Polymorphism, Single Nucleotide
• Real-Time Polymerase Chain Reaction
• Retrospective Studies
• UDP-Glucuronosyltransferase 1A9