Hong-Hao Zhou

Gly389Arg polymorphism of β1‐adrenergic receptor is associated with the cardiovascular response to metoprolol

Our objectives were to determine whether the Gly389 polymorphism of the β1‐adrenergic receptor exhibits reduced responsiveness in vivo and to test the hypothesis that the Gly389Arg polymorphism affects the blood pressure and heart rate response to metoprolol.

St John's wort induces both cytochrome P450 3A4–catalyzed sulfoxidation and 2C19–dependent hydroxylation of omeprazole

St Johns wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St Johns wort to induce cytochrome P450 (CYP) 3A4–mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St Johns wort on the pharmacokinetic profiles of omeprazole and its metabolites.

Β1-Adrenergic receptor polymorphisms influence the response to metoprolol monotherapy in patients with essential hypertension

The human β1‐adrenergic receptor, an important therapeutic target in cardiovascular diseases, has 2 common functional polymorphisms (Ser49Gly and Gly389Arg). Our study aimed to confirm that β1‐adrenergic receptor polymorphisms affect the blood pressure response to metoprolol monotherapy in the Chinese population with hypertension.

Pharmacokinetics of sertraline in relation to genetic polymorphism of CYP2C19

Our objective was to evaluate the relationship between the disposition of sertraline and the presence of the CYP2C19 gene and to define the contribution of cytochrome P450 2C19 (CYP2C19) to sertraline N‐demethylation.

Effect of the gene dosage of CYP2C19 on diazepam metabolism in Chinese subjects

To determine whether the gene dosage of CYP2C19 affects the metabolism of diazepam and desmethyldiazepam in healthy Chinese subjects.

Plasma caffeine metabolite ratio (17X/137X) in vivo associated with G-2964A and C734A polymorphisms of human CYP1A2

Either G-2964 or A734 in the human CYP1A2 gene was confirmed to be associated with high inducible enzyme activity in smokers, but not in nonsmokers. In this study, for the first time, we observed an association between phenotypes and genotypes of CYP1A2 with respect to the two genetic polymorphisms in 163 healthy Chinese volunteers living in Qidong. The ratio of plasma 17X/137X at 6 h after oral administration of 300 mg caffeine was employed in CYP1A2 phenotyping analysis, while genotyping analysis was carried out by polymerase chain reaction-restriction fragment length polymorphism. The allele frequencies of A at -2964 and A at 734 in 139 non-smoking subjects were 0.25 and 0.67, respectively. The A/A-2964C/C734, G/A-2964C/C734 or A/A-2964C/A734 genotype that was thought to have lower inducibility/activity of CYP1A2 than the other genotypes did not exist in the tested Chinese subjects. The ratio of 17X/137X was 0.46 +/- 0.26 in G/G-2964A/A734 genotypes (n = 22) and 0.36 +/- 0.19 in non-G/G-2964A/A734 (n = 117). In addition, there was significant difference between them (P = 0.036). A similar result was also achieved in 24 smokers. Since Qidong is a special region with particularly high incidence of hepatocellular carcinoma in China, the association of phenotypes with genotypes of CYP1A2 in the Qidong population might result from some inducible environmental factors such as those of cigarettes in smokers.

Identification and Functional Characterization of Genetic Variants of Human Organic Cation Transporters in a Korean Population

Genetic variants of three human organic cation transporter genes (hOCTs) were extensively explored in a Korean population. The functional changes of hOCT2 variants were evaluated in vitro, and those genetic polymorphisms of hOCTs were compared among different ethnic populations. From direct DNA sequencing, 7 of 13 coding variants were nonsynonymous single-nucleotide polymorphisms (SNPs), including four variants from hOCT1 (F160L, P283L, P341L, and M408V) and three from hOCT2 (T199I, T201M, and A270S), whereas 6 were synonymous SNPs. The linkage disequilibrium analysis presented for three independent LD blocks for each hOCT gene showed no significant linkage among all three hOCT genes. The transporter activities of MDCK cells that overexpress the hOCT2-T199I, -T201M, and -A270S variants showed significantly decreased uptake of [3H]methyl-4-phenylpyridinium acetate (MPP+) or [14C]tetraethylammonium compared with those cells that overexpress wild-type hOCT2, and the estimated kinetic parameters of these variants for [3H]MPP+ uptake in oocytes showed a 2- to 5-fold increase in Km values and a 10- to 20-fold decrease in Vmax values. The allele frequencies of the five functional variants hOCT1-P283L, -P341L, and hOCT2-T199I, -T201M, and -A270S were 1.3, 17, 0.7, 0.7, and 11%, respectively, in a Korean population; the frequency distributions of these variants were not significantly different from those of Chinese and Vietnamese populations. These findings suggest that genetic variants of hOCTs are not linked among three genes in a Korean population, and several of the hOCT genetic variants cause decreased transport activity in vitro compared with the wild type, although the clinical relevance of these variants remains to be evaluated.

Effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine pharmacokinetics after renal transplantation.

1 The calcineurin inhibitor cyclosporine is widely used to prevent allograft rejection after solid organ transplantation. It has a narrow therapeutic index and shows considerable interindividual differences in its pharmacokinetics. Interindividual differences in the activity and expression of the metabolising enzymes cytochrome P450 (CYP) 3A4 and 3A5 and the multidrug efflux pump P‐glycoprotein (P‐gp) contribute considerably to cyclosporine pharmacokinetics. Variability in the activity of CYP3A4, CYP3A5 and P‐gp could be considered to result from genetic polymorphisms encoding their genes. 2 The aim of the present study was to evaluate retrospectively the effects of genetic polymorphisms of CYP3A4, CYP3A5 and MDR1 on cyclosporine dose adjusted trough blood concentration during the early period after renal transplantation in Chinese patients. 3 One hundred and six renal transplant recipients in China were genotyped by polymerase chain reaction–restriction fragment length polymorphism for CYP3A4*18A, CYP3A5*3 and MDR1 C3435T. Cyclosporine whole blood levels were measured by fluorescence polarization immunoassay. Dose‐adjusted trough blood concentrations (C0) were determined and compared among the different genotype groups. 4 The frequency of the CYP3A4*18A, CYP3A5*3 and MDR1 C3435T variant alleles were 0.005 (95% confidence interval (CI) 0.048, 0.0049), 0.783 (95% CI 0.781, 0.785) and 0.528 (95% CI 0.526, 0.531), respectively, and these alleles exhibited incomplete linkage disequilibrium. The median cyclosporine dose‐adjusted C0 in CYP3A5*1/*1 genotype subjects (n = 6) was 14.8 ng/mL per mg per kg (range 11.1–26.8 ng/mL per mg per kg), in CYP3A5*1/*3 patients (n = 34) it was 23.7 ng/mL per mg per kg (range 9.0–61.0 ng/mL per mg per kg) and for CYP3A5*3/*3 patients (n = 66) it was 26.4 ng/mL per mg per kg (range 9.8–85.8 ng/mL per mg per kg; P = 0.012, Kruskal–Wallis test). Accordingly, cyclosporine dose‐adjusted C0 was larger in CYP3A5 non‐expressors than expressors in the first week after renal transplantation. In addition, wild‐type homozygotes (n = 21) for MDR1 C3435T had a slight but significantly lower dose‐adjusted C0 compared with heterozygotes (n = 58): 17.7 (10.3–60.8) versus 26.4 (9.0–67.3) ng/mL per mg per kg, respectively (P = 0.014, Mann–Whitney U‐test). 5 In conclusion, the present study shows that genetic polymorphisms in CYP3A5 may be responsible, in part, for the large interindividual variability of cyclosporine pharmacokinetics during the early phase after renal transplantation in Chinese patients. Patients with the CYP3A5*3 variant genotype require a low dose of cyclosporine to reach target levels compared with those with the CYP3A5*1 allele.

The Influence of St. John's Wort on CYP2C19 Activity with Respect to Genotype

Induction of cytochrome P450 isozymes is the major cause for clinical drug interactions of St. Johns wort. The relationships of St. Johns wort to cytochrome P450 isoforms have been fully investigated, but its effect on CYP2C19 is lacking. Thus, the aim of the present study was to observe the effect of St. Johns wort on CYP2C19 activity using CYP1A2 as a control. Twelve healthy adult men—6 extensive metabolizers of CYP2C19 (2C19*1/2C19*1) and 6 poor metabolizers (4 2C19*2/ 2C19*2 and 2 2C19*2/2C19*3)—were enrolled in a two‐phase, randomized, crossover manner. All subjects took a 300‐mg St. Johns wort tablet or placebo three times daily for 14 days, and then the activities of CYP2C19 and CYP1A2 were measured using mephenytoin and caffeine. It was found that St. Johns wort treatment significantly increased CYP2C19 activity in CYP2C19 wild‐genotype subjects, with urinary 4′‐hydroxymephenytoin excretion raised by 151.5% ± 91.9% (p = 0.0156), whereas no significant alteration was observed for CYP2C19 poor metabolizers. Repeated St. Johns wort administration did not affect the CYP1A2 phenotypic ratio for both CYP2C19 genotype subjects. In conclusion, St. Johns wort is an inducer to the human CYP2C19, and clinicians should pay great attention when St. Johns wort is added to or withdrawn from an existing drug regimen containing substrates for such enzymes.

OATP1B1 POLYMORPHISM IS A MAJOR DETERMINANT OF SERUM BILIRUBIN LEVEL BUT NOT ASSOCIATED WITH RIFAMPICIN-MEDIATED BILIRUBIN ELEVATION

1 Elevated serum bilirubin levels are caused mainly by liver diseases, haematolysis, genetic defects and drug intake. Unconjugated bilirubin (UCB) is taken up into hepatocytes by human organic anion transporting polypeptide 1B1 (OATP1B1; encoded for by the SLCO1B1 gene). The present study was performed to determine the association between SLCO1B1 gene polymorphisms and serum bilirubin levels in vivo. Moreover, the effects of administration of low‐dose rifampicin on serum bilirubin levels in different SLCO1B1 genotypes was examined. 2 Serum bilirubin levels were examined in 42 healthy volunteers who had been analysed for SLCO1B1 genotype (seven, 13, 14 and eight with SLCO1B1 genotypes *1a/*1a, *1b/*1b, *1b/*15 and *15/*15, respectively). Among them, 24 subjects (seven, seven, eight and two with SLCO1B1 genotypes *1a/*1a, *1b/*1b, *1b/*15 and *15/*15, respectively) were selected to participate in an open‐label, two‐phase clinical trial. Each was given 450 mg rifampicin orally once daily at 2000 hours for 5 consecutive days. Serum bilirubin concentrations at 0800 hours on the 1st and 6th days were compared between the different SLCO1B1 genotypes. 3 In the 42 volunteers, the mean (±SD) serum UCB in both SLCO1B1*1b/*15 and *15/*15 groups was significantly higher than that in the SLCO1B1*1b/*1b group (11.07 ± 2.31, 13.01 ± 3.87 and 8.21 ± 2.68 µmol/L, respectively; P = 0.009 and P < 0.001). Total bilirum (T.BIL) in both the SLCO1B1*1b/*15 and *15/*15 groups was significantly higher than that in the SLCO1B1*1b/*1b group (16.69 ± 4.09, 20.71 ± 5.12 and 13.06 ± 5.12 µmol/L, respectively; P = 0.029 and P < 0.001). The direct bilirubin (D.BIL) in the SLCO1B1*15/*15 group was significantly higher than that in the SLCO1B1*1b/*1b group (7.69 ± 1.81 vs 4.85 ± 1.81 µmol/L, respectively; P = 0.001). Rifampicin significantly increased UCB, T.BIL and D.BIL concentrations in 24 healthy volunteers (17.68 ± 5.96 vs 13.95 ± 4.44 µmol/L (P = 0.040), 5.72 ± 2.01 vs 4.35 ± 1.50 µmol/L (P = 0.028) and 12.00 ± 4.26 vs 9.61 ± 3.15 µmol/L (P = 0.035), respectively). However, the extent of the increase in serum bilirubin caused by 450 mg rifampicin for 5 days was not affected by SLCO1B1 genotype. 4 Genetic polymorphism in SLCO1B1 is a major determinant of interindividual variability in the serum bilirubin level. SLCO1B1*15 carriers had higher baseline serum UCB, T.BIL and D.BIL levels compared with subjects with the SLCO1B1*1a/*1a and SLCO1B1*1b/*1b genotypes. SLCO1B1*15/*15 homozygotes are more susceptible to hyperbilirubinaemia. Serum bilirubin levels could be increased by low‐dose rifampicin administration, but the extent of the increase was not associated with SLCO1B1 genotype.