Dong-Li Hu

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.

Effects of Ginkgo biloba Extract Ingestion on the Pharmacokinetics of Talinolol in Healthy Chinese Volunteers

Background Ginkgo biloba extract (GBE), the best selling herbal medicine in the world, has been reported to inhibit P-glycoprotein in vitro. However, the effects of GBE on P-glycoprotein activity in humans have not been clarified. Objective To investigate the effects of single and repeated GBE ingestion on the oral pharmacokinetics of talinolol, a substrate drug for P-glycoprotein in humans. Methods Ten unrelated healthy male volunteers were selected to participate in a 3-stage sequential study. Plasma concentrations of talinolol from 0 to 24 hours were measured by high-performance liquid chromatography after talinolol 100 mg was administrated alone, with a single oral dose of GBE (120 mg), and after 14 days of repeated GBE ingestion (360 mg/day). Results A single oral dose of GBE did not affect the pharmacokinetics of talinolol. Repeated ingestion of GBE increased the talinolol maximum plasma concentration (Cmax) by 36% (90% CI 10 to 68; p = 0.025), the area under the concentration-time curve (AUC)0-24 by 26% (90% CI 11 to 43; p = 0.008) and AUC0-∞ by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to Cmax. Conclusions Our results suggest that long-term use of GBE significantly influenced talinolol disposition in humans, likely by affecting the activity of P-glycoprotein and/or other drug transporters.

Effect of Schisandra chinensis extract and Ginkgo biloba extract on the pharmacokinetics of talinolol in healthy volunteers.

The authors investigated the effect of herbal medicine Schisandra chinensis extract (SchE) and Ginkgo biloba extract (GBE) on the oral pharmacokinetics of P-glycoprotein substrate talinolol in humans. Twelve healthy male volunteers took a single 100-mg oral dose of talinolol either alone or after pretreatment with 300 mg SchE twice daily or with 120 mg GBE three times daily for 14 days. On day 14, a single 100-mg oral dose of talinolol was administered. Plasma concentrations of talinolol from zero to 24 h were measured by high-performance liquid chromatography. SchE increased the area under the curve (AUC)0–24 of talinolol by 47% (90% confidence interval (CI), 18–84%; p = 0.010), and GBE by 21% (90% CI = 11–32%; p = 0.002). The Cmax of talinolol increased by 51% (90% CI = 21–89%; p = 0.007) with SchE treatment and by 33% (90% CI = 18–51%; p = 0.002) with GBE treatment, respectively. The t1/2 of talinolol increased by 7% (90% CI = −4% to 19%; p = 0.320) with SchE treatment and by 11% (90% CI = −12% to 38%; p = 0.436) with GBE treatment, respectively. The results suggest that both SchE and GBE significantly inhibited P-glycoprotein in humans. Patients receiving either SchE or GBE may require dose adjustments when treated with drugs primarily transported by P-glycoprotein.

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

Background: Curcumin is a kind of plant polyphenol that is extracted from the rhizome of Curcuma longa. Studies about the effect of curcumin on the activity of drug-metabolizing enzymes in humans are lacking. Objective: To investigate the effect of curcumin on the activities of CYP1A2, CYP2A6, N-acetyltransferase (NAT2), and xanthine oxidase (XO) in vivo, using caffeine as a probe drug. Method: Sixteen unrelated, healthy Chinese men were recruited for the study. There were 2 phases in the study. In the first phase, volunteers orally received 100 mg caffeine and 0- to 12-hour blood and urine samples were collected. In the second phase, volunteers received 1000 mg curcumin once daily for 14 continuous days, and blood and urine samples were collected on day 15, following the same procedure used on the first day. Urinary caffeine metabolite ratios were used as the indicators of the activities of CYP1A2, CYP2A6, NAT2, and XO. The pharmacokinetics of caffeine and its metabolites were determined by high-performance liquid chromatography. Results: In the curcumin-treated group, CYP1A2 activity was decreased by 28.6% (95% CI 15.6 to 41.B; p < 0.000), while increases were observed in CYP2A6 (by 48.9%; 95% CI 25.3 to 72.4; p < 0.000). Plasma area under the curve from zero to 12 hours of 1,7-dimethylxanthine (17X) was decreased by 27.2% (95% CI 6.1 to 48.3; p = 0.014). The urinary excretion of 17X and 1-methylxanthine was significantly decreased by 36.4% (95% C119.4 to 53.6; p < 0.000) and 31.2% (95% CI 8.5 to 54.1; p = 0.010), respectively. The excretion of 1,7-dimethylurate (17U) was significantly increased by 77.3% (95% CI 5.6 to 148.8; p = 0.036). No significant changes were observed for caffeine, 1-methylurate, and 5-acetyiamino-6-formylamino-3-methyluracil between the 2 study phases. Conclusions: The results indicated that curcumin inhibits CYP1A2 function but enhances CYP2A6 activity. Simultaneously, some pharmacokinetic parameters relating lo 17X were affected by curcumin. If this finding is confirmed by other studies, the possibility of herb-drug interactions associated with curcumin should be considered in clinical practice,

Clopidogrel Inhibits CYP2C19‐Dependent Hydroxylation of Omeprazole Related to CYP2C19 Genetic Polymorphisms

This study explores the impact of clopidogrel on the pharmacokinetics of omeprazole related to CYP2C19 genetic polymorphisms. Twelve healthy volunteers (6 CYP2C19*1/*1, 5 CYP2C19*2/*2, and 1 CYP2C19*2/*3) are enrolled in a 2‐phase randomized crossover trial. In each phase, the volunteers are administered a single oral dose of omeprazole 40 mg after pretreatment of either placebo or clopidogrel (300 mg on the first day and then 75 mg once daily for 3 consecutive days). Plasma concentrations of omeprazole and its metabolites are quantified by high‐performance liquid chromatography with UV detection. After clopidogrel treatment, the AUC0–∞ of omeprazole increases by 30.02% ± 18.03% (P = .004) and that of 5‐hydroxyomeprazole decreases by 24.30% ± 11.66% (P = .032) in CYP2C19*1/*1. The AUC0–∞ ratios of omeprazole to 5‐hydroxyomeprazole increase by 74.98% ± 35.48% (P = .001) and those of omeprazole to omeprazole sulfone do not change significantly (P = .832) in CYP2C19*1/*1. No significant alteration is observed in CYP2C19*2/*2 or *3. Clopidogrel inhibits CYP2C19‐dependent hydroxylation of omeprazole in CYP2C19*1/*1 and has no impact on CYP3A4‐catalyzed sulfoxidation of omeprazole.

Effects of the CYP2C9*13 allele on the pharmacokinetics of losartan in healthy male subjects

The aim of the study was to determine the pharmacokinetics of losartan in relation to the CYP2C9*13 allele. A single oral dose of 50 mg losartan was administrated to each of the 16 healthy male volunteers with a different genotype (CYP2C9*1/*1, n = 6; CYP2C9*1/*13, n = 4; and CYP2C9*1/*3, n = 6). Blood samples were collected from pre-dose up to 24 h after the drug administration. Plasma losartan and E3174 (an active metabolite of losartan) were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). All the subjects finished the study without adverse drug effects. In the present study, the frequencies of CYP2C9*13 and *13 alleles were 0.6% and 2.6% in Chinese healthy volunteers, respectively, and both alleles were in Hardy–Weinberg equilibrium. Compared with the subjects in the CYP2C9*1/*1 group, individuals carrying the CYP2C9*1/*13 genotype showed significantly a longer t1/2 of losartan and E3174 and markedly increased the area under the curve (AUC) of losartan. Meanwhile, the CYP2C9*1/*3 genotype group had significant differences in t1/2 and Cmax of E3174 compared with the CYP2C9*1/*1 group. The ratio of AUCE3174/AUClosartan after losartan administration in the CYP2C9*1/*13 and CYP2C9*1/*3 groups was also statistically different from that in the CYP2C9*1/*1 group. The data indicate that the presence of the CYP2C9*13 allele results in poor metabolism of losartan after a single oral dose.

Effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers.

AIMS To assess the effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers. METHODS Fourteen healthy male volunteers (age range 19-25 years) received orally administered bupropion (150 mg) alone and during treatment with G. biloba 240 mg day(-1) (two 60-mg capsules taken twice daily) for 14 days. Serial blood samples were obtained over 72 h after each bupropion dose, and used to derive pharmacokinetic parameters of bupropion and its CYP2B6-catalysed metabolite, hydroxybupropion. RESULTS Ginkgo biloba extract administration resulted in no significant effects on the AUC(0-infinity) of bupropion and hydroxybupropion. Bupropion mean AUC(0-infinity) value was 1.4 microg.h ml(-1)[95% confidence interval (CI) 1.2, 1.6] prior to G. biloba treatment and 1.2 microg.h ml(-1) (95% CI 1.1, 1.4) after 14 days of treatment. Hydroxybupropion mean AUC(0-infinity) value was 8.2 microg.h ml(-1) (95% CI 6.5, 10.4) before G. biloba administration and 8.7 microg.h ml(-1) (95% CI 7.1, 10.6) after treatment. The C(max) of hydroxybupropion increased from 221.8 ng ml(-1) (95% CI 176.6, 278.6) to 272.7 ng ml(-1) (95% CI 215.0, 345.8) (P = 0.038) and the t(1/2) of hydroxybupropion fell from 25.0 h (95% CI 22.7, 27.5) to 21.9 h (95% CI 19.9, 24.1) (P = 0.000). CONCLUSIONS Ginkgo biloba extract administration for 14 days does not significantly alter the basic pharmacokinetic parameters of bupropion in healthy volunteers. Although G. biloba extract treatment appears to reduce significantly the t(1/2) and increase the C(max) of hydroxybupropion, no bupropion dose adjustments appear warranted when the drug is administered orally with G. biloba extract, due to the lack of significant change observed in AUC for either bupropion or hydroxybupropion.

Effect of glycyrrhizin on CYP2C19 and CYP3A4 activity in healthy volunteers with different CYP2C19 genotypes

The objective of this study was to investigate the interaction between glycyrrhizin and omeprazole and observe the effects of glycyrrhizin on CYP2C19 and CYP3A4 activities in healthy Chinese male volunteers with different CYP2C19 genotypes. Eighteen healthy subjects (six CYP2C19*1/*1, five CYP2C19*1/*2, one CYP2C19*1/*3, five CYP2C19*2/*2 and one CYP2C19*2/*3) were enrolled in a two-phase randomized crossover trial. In each phase, all subjects received placebo or glycyrrhizin salt tablet 150 mg twice daily for 14 consecutive days. The pharmacokinetics of omeprazole (20 mg orally on day 15) was determined for up to 12 h following administration by high-performance liquid chromatography. After 14-day treatment of glycyrrhizin, plasma omeprazole significantly decreased, and those of omeprazole sulfone significantly increased. However, plasma concenetrations of 5-hydroxyomeprazole did not significantly change. The ratio of AUC0–∞ of omeprazole to omeprazole sulfone decreased by 43.93% ± 13.56% (p = 0.009) in CYP2C19*1/*1, 44.85% ± 14.84% (p = 0.002) in CYP2C19*1/*2 or *3 and 36.16% ± 7.52% (p < 0.001) in CYP2C19*2/*2 or *3 while those of omeprazole to 5-hydroxyomeprazole did not change significantly in all three genotypes. No significant differences in glycyrrhizin response were found among CYP2C19 genotypes. Glycyrrhizin induces CYP3A4-catalyzed sulfoxidation of omeprazole and leads to decreased omeprazole plasma concentrations, but has no significant impact on CYP2C19-dependent hydroxylation of omeprazole.

Hepatic Nuclear Factor 1α Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin

Expression of the organic anion transporting polypeptide 1B1 (OATP1B1) is regulated by transcription factor hepatic nuclear factor (HNF) 1α. The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA), an inhibitor of transcription factor HNF1α, on rosuvastatin and bilirubin kinetics in human healthy volunteers. Both substances are substrates of OATP1B1. Twelve subjects with OATP1B1*1b/*1b genotype predicting high transport activity were recruited for this randomized, crossover study. Each subject received a single p.o. dose of 20 mg of rosuvastatin after 14 days of p.o. intake of either 500 mg of UDCA or placebo. Plasma concentrations of rosuvastatin were determined on days 15 to 18 of each study period. Subjects were randomly assigned to UDCA or placebo group. Intake of UDCA led to a significant increase in rosuvastatin area under the curve (AUC)0–72 from 128.5 ng/ml · h to 182.1 ng/ml · h(P = 0.008) compared with the control group. The oral clearance decreased from 155.2 l/h with placebo to 109.8 l/h with UDCA. In addition, the mean values of total bilirubin, conjugated bilirubin, and unconjugated bilirubin significantly increased to 139 ± 39% (P = 0.003), 127 ± 29% (P = 0.005), and 151 ± 52% (P = 0.004), respectively, after UDCA treatment. These results in healthy volunteers confirm the findings from in vitro studies that UDCA inhibits OATP1B1 activity by inhibition of the transcription factor HNF1α. They highlight a novel mechanism of OATP1B1-based interaction that is mediated by transcription factor HNF1α.

Herbal medicine Yin Zhi Huang induces CYP3A4-mediated sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole

AbstractAim:To explore the potential interactions between Yin Zhi Huang (YZH) and omeprazole, a substrate of CYP3A4 and CYP2C19.Methods:Eighteen healthy volunteers, including 6 CYP2C19*1/*1, 6 CYP2C19*1/*2 or *3 and 6 CYP2C19*2/*2 were enrolled in a 2-phase, randomized, crossover clinical trial. In each phase, the volunteers received either placebo or 10 mL YZH oral liquid, 3 times daily for 14 d. Then all the patients took a 20 mg omeprazole capsule orally. Blood samples were collected up to 12 h after omeprazole administration. Plasma concentrations of omeprazole and its metabolites were quantified by HPLC with UV detection.Results:After 14 d of treatment of YZH, plasma omeprazole significantly decreased and those of omeprazole sulfone and 5-hydroxyomeprazole significantly increased. The ratios of the area under the plasma concentration-time curves from time 0 to infinity (AUC(0-∞) of omeprazole to 5-hydroxyomprazole and those of omeprazole to omeprazole sulfone decreased by 64.80%±12.51% (P=0.001) and 63.31%±18.45% (P=0.004) in CYP2C19*1/*1, 57.98%±14.80% (P=0.002) and 54.87%±18.42% (P =0.003) in CYP2C19*1/*2 or *3, and 37.74%±16.07% (P=0.004) and 45.16%±15.54% (P=0.003) in CYP2C19*2/*2, respectively. The decrease of the AUC(0-∞) ratio of omeprazole to 5-hydroxyomprazole in CYP2C19*1/*1 and CYP2C19*1/*2 or *3 was greater than those in CYP2C19*2/*2 (P=0.047 and P=0.009).Conclusion:YZH induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole leading to decreases in plasma omeprazole concentrations.