Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
AAPS J ; 16(2): 206-13, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24357089

ABSTRACT

To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25% ∼ 64%), increased area under the plasma level-time curves (30~76%), increased area under the time infinity (43% ∼ 80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Glucuronosyltransferase/metabolism , Indapamide/pharmacokinetics , Polymorphism, Single Nucleotide , Chromatography, High Pressure Liquid , Gene Frequency , Healthy Volunteers , Humans , Linkage Disequilibrium , Mass Spectrometry , Taiwan
2.
Pharmacogenet Genomics ; 23(4): 200-7, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23407048

ABSTRACT

BACKGROUND: Earlier studies have demonstrated an association between N-acetyltransferase 2 (NAT2) catalytic activity and the genotype of a recently published tag single nucleotide polymorphism (SNP), rs1495741. There have been no reports on the relationship between the rs1495741 genotype and antituberculosis drug-induced hepatotoxicity (ATDIH) to date. OBJECTIVE: The aim of the present study was to determine the frequency of the NAT2 tag SNP (rs1495741) in the Taiwanese and its relation to the incidence of ATDIH. MATERIALS AND METHODS: A total of 348 tuberculosis patients were enrolled to determine the frequency of NAT2 tag SNP rs1495741 and its relation to the incidence of ATDIH. The conventional NAT2 variants alleles have also been investigated. Furthermore, to evaluate the correlation of NAT2 activity and rs1495741 genotypes, a pharmacokinetic study of isoniazid was also conducted in healthy volunteers. RESULTS: Among the 348 tuberculosis patients, 20 (5.7%) were diagnosed with ATDIH. The frequencies of the three rs1495741 genotypes, viz., AA, AG, and GG, were 24.7, 52.3, and 23.0%, respectively. Significant differences among rs1495741 genotypes and susceptibility to hepatotoxicity were noted (odds ratio=14.068, P<0.05). Moreover, the rs1495741 genotypes showed an association with the isoniazid dosage required for induction of hepatotoxicity. In the pharmacokinetic study, NAT2 activity was strongly associated with genotype categories (P<0.001). CONCLUSION: The present study demonstrated that the three genotypes according to rs1495741 were in good accordance with conventional NAT2 alleles-inferred phenotypes and the tag SNP could be used as a proxy to determine the susceptibility to ATDIH.


Subject(s)
Arylamine N-Acetyltransferase/genetics , Chemical and Drug Induced Liver Injury/genetics , Genetic Predisposition to Disease , Tuberculosis/drug therapy , Adult , Aged , Alleles , Antitubercular Agents/administration & dosage , Antitubercular Agents/adverse effects , Chemical and Drug Induced Liver Injury/complications , Female , Genetic Association Studies , Humans , Isoniazid/administration & dosage , Isoniazid/adverse effects , Male , Middle Aged , Polymorphism, Single Nucleotide , Tuberculosis/complications , Tuberculosis/pathology
SELECTION OF CITATIONS
SEARCH DETAIL
...