Zhi-Rong Tan

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.

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.

Assessment of cytochrome P450 activity by a five-drug cocktail approach

Our goal was to establish and validate a modified cocktail approach including probe drugs caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam for simultaneous phenotyping of CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A.

Rifampicin alters atorvastatin plasma concentration on the basis of SLCO1B1 521T>C polymorphism.

BACKGROUND Both atorvastatin and rifampicin are substrates of OATP1B1 (organic anion transporting polypeptide 1B1) encoded by SLCO1B1 gene. Rifampicin is a potent inhibitor of SLCO1B1 (IC50 1.5 umol/l) and SLCO1B1 521T>C functional genetic polymorphism alters the kinetics of atorvastatin in vivo. We hypothesize that rifampicin might influence atorvastatin kinetics in a SLCO1B1 polymorphism dependent manner. METHODS Sixteen subjects with known SLCO1B1 genotypes (6 c.521TT, 6 c.521TC and 4 c.521CC) were divided into 2 groups (atorvastatin-placebo group, n=8; atorvastatin-rifampicin group, n=8) randomly. In this 2-phase crossover study, atorvastatin (40 mg single-oral dose) pharmacokinetics after co-administration of placebo and rifampicin (600 mg single-oral dose) were measured for up to 48 h by liquid chromatography-mass spectrometry (LC-MS). In the third phase, rifampicin (450 mg single-oral dose) pharmacokinetics was measured additionally. RESULTS Rifampicin increased atorvastatin plasma concentration in accordance with SLCO1B1 521T>C genotype while the increasing percentage of AUC((0-48)) among c.521TT, c.521TC and c.521CC individuals were 833+/-245% vs 468+/-233% vs 330+/-223% (P=0.007). However, SLCO1B1 521T>C exerted no impact on rifampicin pharmacokinetics (P>0.05). CONCLUSIONS These results suggested that rifampicin elevated the plasma concentration of atorvastatin depending on SLCO1B1 genotype and rifampicin pharmacokinetics were not altered by SLCO1B1 genotype.

The Effect of Herbal Medicine Baicalin on Pharmacokinetics of Rosuvastatin, Substrate of Organic Anion-transporting Polypeptide 1B1

The aim of this study was to explore potential herb–drug interaction between baicalin and rosuvastatin, a typical substrate for organic anion‐transporting polypeptide 1B1 (OATP1B1) related to different OATP1B1 haplotype groups. Eighteen unrelated healthy volunteers who were CYP2C9*1/*1 with different OATP1B1 haplotypes (six OATP1B1*1b/*1b, six OATP1B1*1b/*15, and six OATP1B1*15/*15) were selected to participate in this study. Rosuvastatin (20 mg orally) pharmacokinetics after coadministration of placebo and 50‐mg baicalin tablets (three times daily orally for 14 days) were measured for up to 72 h by liquid chromatography–mass spectrometry in a two‐phase randomized crossover study. After baicalin treatment, the area under the plasma concentration–time curve (AUC)(0–72) and AUC(0–∞) of rosuvastatin decreased by 47.0±11.0% (P=0.001) and 41.9±7.19% (P=0.001) in OATP1B1*1b/*1b, 21.0±20.6% (P=0.035) and 23.9±8.66% (P=0.004) in OATP1B1*1b/*15, and 9.20±11.6% (P=0.077) and 1.76±4.89% (P=0.36) in OATP1B1*15/*15, respectively. Moreover, decreases of both AUC(0–72) and AUC(0–∞) of rosuvastatin among different haplotype groups were significantly different (P=0.002 and <0.001). Baicalin reduces plasma concentrations of rosuvastatin in an OATP1B1 haplotype–dependent manner.

Association of CYP3A4*18B polymorphisms with the pharmacokinetics of cyclosporine in healthy subjects

The aim of this study is to evaluate the association of the CYP3A4*18B genotype with the cyclosporine metabolism in healthy subjects. We employed PCR–RFLP assays for analysis of the CYP3A4*18B genotype. Each of 26 subjects, comprising 12 CYP3A4*1/*1, 12 CYP3A4*1/*18B and 2 CYP3A4*18B/*18B, was given a single oral dose of cyclosporine (4 mg kg−1). The plasma concentrations of cyclosporine were measured for up to 24 h post dose by high-performance liquid chromatography–electrospray mass spectrometry. We found that the mean Cmax (95% confidence intervals) of cyclosporine were 2237 (2905, 1859) (*1/*1), 2247 (2916, 1869) (*1/*18B), and 905 (1192, 506) ng ml−1 (*18B/*18B) (p = 0.037) and the mean AUC0-4 were 5026 (6181, 4372) (*1/*1), 4434 (5481, 3841) (*1/*18B) and 2561 (3155, 1736) ng ml-1 h (*18B/*18B) (p = 0.021). The CL in the *18B/*18B group was significantly higher than in the *1/*1 group. However, Tmax exhibited no difference among the three genotypes. *18B/*18B group showed 50% reduction in concentration at 2 h post dose compared with *1/*18B (p = 0.062) or *1/*1 (p = 0.047), but no statistical significance was detected between*1/*1 and *1/*18B groups (p > 0.05). The data suggest that the CYP3A4*18B genotype affects cyclosporine pharmacokinetics probably resulting from a higher enzymatic activity of this mutation in healthy subjects.

Lack of Effect of Ginkgo biloba on Voriconazole Pharmacokinetics in Chinese Volunteers Identified as CYP2C19 Poor and Extensive Metabolizers

Background: Ginkgo biloba is one of the most popular herbal supplements in the world. The supplement has been shown to induce the enzymatic activity of CYP2C19, the main cytochrome P450 isozyme involved in voriconazole metabolism. Because this enzyme exhibits genetic polymorphism, the inductive effect was expected to be modulated by the CYP2C19 metabolizer status. Objective: To examine the possible effects of Ginkgo biloba as an inducer of CYP2C19 on single-dose pharmacokinetics of voriconazole in Chinese volunteers genotyped as either CVP2C19 extensive or poor metabolizers. Methods: Fourteen healthy, nonsmoking volunteers–7 CYP2C19 extensive metabolizers (2C19*1/2C19*1) and 7 poor metabolizers (2C19*2/2C19*2)–were selected to participate in this study. Pharmacokinetics of oral voriconazole 200 mg after administration of Ginkgo biloba 120 mg twice daily for 12 days were determined for up to 24 hours by liquid chromatography–electrospray tandem mass spectrometry in a 2-phase randomized crossover study with 4-week washout between phases. Results: For extensive metabolizers, the median value for voriconazole area under the plasma concentration–time curve from zero to infinity (AUC0-00) was 5.17 μg•h/mL after administration of voriconazole alone and 4.28 μg•/mL after voriconazole with Ginkgo biloba (p > 0.05). The other pharmacokinetic parameters of voriconazole such as AUC0-24, time to reach maximum concentration, half-life, and apparent clearance also did not change significantly for extensive metabolizers in the presence of Ginkgo biloba. Pharmacokinetic parameters followed a similar pattern for poor metabolizers. Conclusions: The results suggest that 12 days of treatment with Ginkgo biloba did not significantly alter the single-dose pharmacokinetics of voriconazole in either CYP2C19 extensive or poor metabolizers. Therefore, the pharmacokinetic interactions between voriconazole and Ginkgo biloba may have limited clinical significance.

Effect of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 in healthy Chinese volunteers.

PurposeTo investigate the effects of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 and its relationship with CYP2C9 genotypes.MethodsTwelve healthy adult men of known CYP2C9 genotype (six CYP2C9*1/*1 and six CYP2C9*1/*3) were recruited in a two-phase randomized crossover design study. The pharmacokinetics of losartan and E-3174 were measured before and after a 14-day treatment with 140 mg of silymarin three times daily.ResultsThe area under the plasma concentration–time curve (AUC) of losartan increased significantly following a 14-day silymarin treatment in subjects with the CYP2C9*1/*1 genotype, but not in those with the CYP2C9*1/*3 genotype. The AUC of E-3174 decreased significantly with a silymarin pretreatment in both CYP2C9*1/*1 and the CYP2C9*1/*3 subjects. The metabolic ratio of losartan (ratio of

Plant polyphenol curcumin significantly affects CYP1A2 and CYP2A6 activity in healthy, male Chinese volunteers.

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