[Show abstract][Hide abstract] ABSTRACT: To detect 388G>A and 521T>C variant alleles in the organic anion transporting polypeptide-1B1 (OATP1B1, encoding gene SLCO1B1) gene.
One hundred and eleven healthy volunteers were screened for OATP1B1 alleles in our study. PCR-restriction fragment length polymorphism was used to identify the 388G>A polymorphism and a 1-step tetra-primer method was developed for the determination of 521T>C mutation.
The frequencies of the 388G>A and 521T>C variant alleles in the Chinese population were 73.4% and 14.0%, respectively. The frequencies of the SLCO1B1*1b and *15 haplotypes were 59.9% and 14.0%, respectively.
The SLCO1B1*1b and SLCO1B1*15 variants are relatively common in the Chinese population. Their frequencies are similar to that in the Japanese, but significantly different from that in Caucasians and blacks.
Preview · Article · Nov 2007 · Acta Pharmacologica Sinica
[Show abstract][Hide abstract] ABSTRACT: P-glycoprotein is localized at the apical brush-border membrane of the proximal renal tubule and functions as extruding toxins and xenobiotics out of cells. The difference of P-glycoproteinos function resulted from single nucleotide polymorphisms in MDR1 (multidrug resistance gene encoding for P-gp) and may be the cause of interindividual differences in susceptibility to end-stage renal disease (ESRD). The purpose of this study is to compare the genotype frequency of C3435T and G1199A polymorphisms in MDR1 between ESRD patients and healthy controls in the Chinese population to determine whether the alteration of the P-gp function is associated with ESRD.
Two hundred and eighty-four healthy Chinese controls and 244 Chinese patients with ESRD were involved in this study. Allele specific PCR and polymerase chain reaction-restriction fragment length polymorphism assay were used to determine the genotype MDR1 G1199A and C3435T, respectively.
The genotype distribution of 3435CC, 3435CT, and 3435TT were 0.35, 0.50, and 0.15, respectively, in the control group and 0.38, 0.47, and 0.15 in the group with the ESRD patients. No variant allele 1199G>A was found in any of the patients. The value of serum creatinine for genotypes 3435CC, 3435CT, and 3435TT in the ESRD patients were 753.8+/-276.0 mumol/L, 849.6+/-342.2 micromol/L, and 987.0+/-512.0 micromol/L, respectively. The difference between 3435TT and 3435CC reached statistical significance (P<0.05).
The low expression of P-glycoprotein was not the etiological factor for the kidney disease, but it may contribute to the progression of ESRD and affect the severity. Chinese people do not carry the 1199G>A variant allele. More studies are needed to clarify the cause and interindividual differences in the susceptibility for the risk of ESRD.
[Show abstract][Hide abstract] ABSTRACT: To investigate the pharmacokinetics of mycophenolic acid (MPA), an active metabolite of mycophenolate mofetil (MMF) in Chinese adult liver transplant patients.
Thirty-eight liver transplant patients (male 30, female 8) receiving MMF 1.0 g, twice daily in accordance with the recommended regimen were included in this study. Plasma MPA concentrations were measured by high performance liquid chromatography at 0.5, 1, 1.5, 2, 4, 6, 8, 10 and 12 h after the administration of a single dose. Pharmacokinetic parameters were calculated with 3P97 software.
The plasma MPA concentration-time curve was characterized with an early sharp peak reached at 0.5 - 6.0 h after oral administration. And in some patients there was a small second peak due to enterohepatic circulation of mycophenolic acid glucuronide (MPAG), which underwent deglucuronidation and re-absorption as MPA at 4 to 12 h postdose. The mean peak plasma concentration (C(max)) and area under concentration-time curve (AUC(0-12 h)) were (12 +/- 7) microg x mL(-1) and (44 +/- 16) microg x h x mL(-1), respectively. However, a large variability of pharmacokinetic parameters existed in these patients.
In view of the inter-individual variability of MMF pharmacokinetics, plasma MPA concentration should be monitored routinely after MMF administration for individual patient.
No preview · Article · Jan 2007 · Yao xue xue bao = Acta pharmaceutica Sinica
[Show abstract][Hide abstract] ABSTRACT: Nateglinide is a meglitinide analogue with antidiabetic action. A recent study showed that SLCO1B1 (which codes the OATP1B1 gene, also known as OATP-C, OATP2) is a major determinant which markedly affects the pharmacokinetics of repaglinide. Our objective was to assess the association between single nucleotide polymorphisms (SNPs) of SLCO1B1 and the pharmacokinetics of nateglinide.
Seventeen healthy volunteers with different SLCO1B1 genotypes (11 with 521TT, four with 521TC and two with 521CC) were enrolled in this study. Each was given a single oral dose of 90 mg nateglinide. Plasma concentrations of nateglinide were measured up to 8 h by HPLC.
The C(max) and AUC(0,infinity) of nateglinide were 83% (P = 0.002) and 82% (P = 0.001) higher in the SLCO1B1521TC subjects (n = 4), and 76% (P = 0.016) and 108% (P = 0.001) higher in the SLCO1B1521CC subjects (n = 2) than in the SLCO1B1521TT subjects (n = 11), respectively. The t(1/2) of nateglinide in SLCO1B1521CC subjects was 78% longer than that in 521TT subjects (P = 0.036). The difference in t(max) values among the three genotypic groups was not statistically significant.
Our results suggest that OATP1B1-mediated hepatic uptake of nateglinide may be the prior step for its metabolism and elimination. SLCO1B1521T > C SNP might play an important role in the pharmacokinetics of nateglinide.
Preview · Article · Dec 2006 · British Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: To determine the phenotype and genotype of NAT2 in a Chinese population and study the influence of various NAT2 genotypes on the NAT2 activity.
A reverse dot blot method was used to detect the genotype of NAT2 in 120 healthy Chinese subjects. All subjects were given a single dose of 500 mg sulphadimidine (SM(2)). The plasma concentration of SM(2) and acetyl-SM(2) (AcSM(2)) 6 h after administration was determined. Molar metabolic ratio (MR) was calculated by the ratio of AcSM(2) to AcSM(2)+SM(2).
Totals of 53 (44.2%), 47 (39.2%) and 20 (16.7%) subjects were homozygotes for wild type (wt/wt), heterozygotes for mutant (m/wt) and homozygotes for mutant (m/m), respectively. The MR of 120 subjects was 0.714+/-0.237. Twenty subjects (16.7%) were classified as poor metabolizers. All subjects in the m/m group were poor metabolizers. The MRs of the wt/wt, m/wt and m/m groups were 0.886+/-0.060, 0.719+/-0.089 and 0.246+/-0.105 (P<0.001), respectively. There was a significant difference between different NAT2 m/wt genotypes (P<0.001) and m/m genotypes (P<0.001). MR correlated well with NAT2 genotypes (r=0.947).
Various NAT2 genotypes have a significant impact on the metabolic activity of NAT2 in Chinese people.
No preview · Article · May 2006 · European Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: To investigate the association of CYP2C9*3 and *6 with hyperlipidaemia in Chinese.
Four hundred and seventy-six Chinese participated in the study, including 211 uncomplicated hyperlipidaemic patients and 265 healthy controls. PCR-RFLP was used to identify CYP2C9*3 and *6.
CYP2C9*6 was not detected in this study. The allelic frequency of CYP2C9*3 was 0.039 (95% CI 0.022, 0.056). A nonsignificant difference existed in CYP2C9*3 frequencies between males and females (P = 0.605, OR = 1.194, 95% CI 0.610, 2.336), patients and controls (P = 0.063, OR = 0.506, 95% CI 0.244, 1.049) in the total population. However, in the female group, CYP2C9*3 frequency in patients with hyperlipidaemia was significantly lower than that in controls (P < 0.0001, OR = 0.062, 95% CI 0.008, 0.476).
The association of CYP2C9*3 with hyperlipidaemia was specific for females in this Chinese population.
Full-text · Article · Dec 2005 · British Journal of Clinical Pharmacology
[Show abstract][Hide abstract] ABSTRACT: We investigated the linkage between SNPs in exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) of MDR1, and explored the effect of linked polymorphism on the absorption of talinolol after a single oral dose of 100 mg.
The genotype of 192 healthy Chinese volunteers was determined using PCR-RFLP with respect to the MDR1 alleles of interest, C1236T, G2677T/A and C3435T. Linkage disequilibrium was analyzed using PHASE software. Consecutive eligible subjects received a single oral dose of 100 mg talinolol. Venous blood samples were taken at intervals up to 60 h post dose for HPLC analysis of plasma concentration of talinolol to obtain a pharmacokinetic profile.
Linkage disequilibrium existed between exon 21 (G2677T/A) and exon 26 (C3435T), exon 12 (C1236T) and exon 21 (G2677T/A), but not between exon 12 (C1236T) and exon 21 (G2677T/A). AUC (0,3 h), AUC (0, infinity), Cmax and Cmax/AUC (0, infinity), used as indices of talinolol absorption, were not significantly different between the genotype groups of 2677GG/3435TT, 2677TT/3435TT, 2677GT/3435CT and 2677AT/3435CT. For these 4 groups, AUC(0,3 h) were 436.8 +/- 50.1, 510.1 +/- 86.3, 466.1 +/- 77.8 and 437.2 +/- 73.4 (microg x h/l) and the Cmax/AUC (0, infinity) were 0.097 +/- 0.018, 0.093 +/- 0.022, 0.105 +/- 0.014 and 0.102 +/- 0.027 (h(-1)), respectively. (P > 0.05).
The linked MDR1 polymorphisms in exon 21 G2677T/A and exon 26 C3435T apparently did not contribute to the absorptive pharmacokinetics of a single oral dose of 100 mg talinolol.
[Show abstract][Hide abstract] ABSTRACT: Human cytochrome P450 2A13 (CYP2A13) is involved in the activation of numerous toxicants and carcinogens, especially in the metabolic activation of 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major tobacco-specific carcinogen. A functionally significant coding single nucleotide polymorphism (C3375T) in exon 5 of CYP2A13, which results in an amino acid substitution of Arg 257 to Cys, has been recently reported to exist in White, Black, Hispanic, and Asian individuals, with the variant 3375T allele frequencies being 1.9%, 14.4%, 5.8% and 7.7%, respectively. Since genetic background differs between ethnic groups, our present study aims to characterize the CYP2A13 Arg257Cys polymorphism in Chinese.
258 healthy Chinese Han volunteers were involved in this study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was employed to genotype for the Arg257Cys polymorphism.
Of all the 258 subjects, 27 (10.5%) heterozygotes and 1 (0.4%) homozygote for the 257Cys allele were detected. The frequency of the variant 257Cys allele in this Chinese population was 5.6% (95%CI: 4.2-7.0%).
The CYP2A13 Arg257Cys variant represents a common polymorphism in Chinese, with the 257Cys allele frequency being similar to the Hispanic and Asian groups, but significantly lower than the Black.
Full-text · Article · Jun 2004 · Clinica Chimica Acta