Searching the cytochrome p450 enzymes for the metabolism of meranzin hydrate: a prospective antidepressant originating from Chaihu-Shugan-San.

Meranzin hydrate (MH), an absorbed bioactive compound from the Traditional Chinese Medicine (TCM) Chaihu-Shugan-San (CSS), was first isolated in our laboratory and was found to possess anti-depression activity. However, the role of cytochrome P450s (CYPs) in the metabolism of MH was unclear. In this study, we screened the CYPs for the metabolism of MH in vitro by human liver microsomes (HLMs) or human recombinant CYPs. MH inhibited the enzyme activities of CYP1A2 and CYP2C19 in a concentration-dependent manner in the HLMs. The Km and Vmax values of MH were 10.3±1.3 µM and 99.1±3.3 nmol/mg protein/min, respectively, for the HLMs; 8.0±1.6 µM and 112.4±5.7 nmol/nmol P450/min, respectively, for CYP1A2; and 25.9±6.6 µM and 134.3±12.4 nmol/nmol P450/min, respectively, for CYP2C19. Other human CYP isoforms including CYP2A6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 showed minimal or no effect on MH metabolism. The results suggested that MH was simultaneously a substrate and an inhibitor of CYP1A2 and CYP2C9, and MH had the potential to perpetrate drug-drug interactions with other CYP1A2 and CYP2C19 substrates.

Quercetin significantly inhibits the metabolism of caffeine, a substrate of cytochrome P450 1A2 unrelated to CYP1A2*1C (-2964G>A) and *1F (734C>A) gene polymorphisms.

BACKGROUND: Quercetin is abundant in plants and human diets. Previous studies indicated that quercetin inhibited the activity of CYP1A2, and the combination of quercetin with the substrates of CYP1A2 might produce herb-drug interactions. This research aims to determine the effects of quercetin and the CYP1A2 gene polymorphisms, namely, CYP1A2*1C (-2964G>A) and *1F (734C>A), on the metabolism of caffeine. METHOD: The experiment was designed into two treatment phases separated by a 2-week washout period. Six homozygous individuals for the CYP1A2*1C/*1F (GG/AA) genotype and 6 heterozygous individuals for the CYP1A2*1C/*1F (GA/CA) genotype were enrolled in the study. Quercetin capsules (500 mg) were given to each volunteer once daily for 13 consecutive days, and after that, each subject was coadministrated 100 mg caffeine capsules with 500 mg quercetin on the 14th day. Then a series of venous blood samples were collected for HPLC analysis. Correlation was determined between pharmacokinetics of caffeine and paraxanthine with caffeine metabolite ratio. RESULTS: Quercetin significantly affected the pharmacokinetics of caffeine and its main metabolite paraxanthine, while no differences were found in the pharmacokinetics of caffeine and paraxanthine between GG/AA and GA/CA genotype groups. CONCLUSION: Quercetin significantly inhibits the caffeine metabolism, which is unrelated to CYP1A2*1C (-2964G>A) and *1F (734C>A) gene polymorphisms.

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 41.8; 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% CI 19.4 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-acetylamino-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 to 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.

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 soy extract administration on losartan pharmacokinetics in healthy female volunteers.

BACKGROUND: osartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E-3174, which has greater antihypertensive activity than the parent compound. Soy extract has been shown to be an activator of CYP2C9 and CYP3A4 in vitro. Coadministration of soy extract and losartan may therefore alter the pharmacokinetics of losartan and E-3174. OBJECTIVE: To determine whether, when losartan was used in combination with soy extract, a significant pharmacokinetic interaction would be observed in healthy female volunteers. METHODS: Eighteen healthy Chinese female volunteers were recruited. In an open-label, 2-phase study, losartan 50 mg was given to each subject, with and without soy extract. Plasma concentrations of losartan and E-3174 were determined by liquid chromatography-tandem mass spectrometry for 12 and 24 hours, respectively. On day 8 through day 21 of the study, following a 7-day washout period, each subject consumed two 1000-mg Genistein Soy Complex tablets orally after meals, twice daily, for 14 days. On day 22, all volunteers received losartan 50 mg and blood samples were collected again. RESULTS: All subjects completed the study, without adverse drug effects. Over the 14-day pretreatment period, soy extract did not significantly influence the pharmacokinetics of losartan or E-3174. The ratio of the area under the curve of the drug and metabolite after losartan administration, with and without soy extract ingestion, was 0.21 +/- 0.05 and 0.23 +/- 0.05 (mean +/- SD), respectively. The difference was not statistically significant (p = 0.22). CONCLUSIONS: Our data indicate that a significant interaction between soy extract and losartan is unlikely to occur in females.

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 (C(max)) 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 AUC(0-infinity) by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to C(max). 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.

Induction of cytochrome P450 2B6 activity by the herbal medicine baicalin as measured by bupropion hydroxylation.

PURPOSE: This study investigated the effect of the herbal medicine baicalin on bupropion hydroxylation, a probe reaction for CYP2B6 activity related to different CYP2B6 genotype groups. METHOD: Seventeen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6, and 5 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with baicalin. Blood samples were taken up to 72 h after each bupropion dose, and pharmacokinetics profiles were determined on days 1 and 25 for bupropion and hydroxybupropion. RESULT: Baicalin administration increased hydroxybupropion maximum plasma concentration (C(max)) by 73% [90% confidence interval (CI), 44-108%; P < 0.01] and the area under the concentration time curve extrapolated to infinity (AUC(0-infinity)) of hydroxybupropion by 87% (90% CI, 48-137%; P < 0.01), with no change in the elimination half-life of hydroxybupropion. Baicalin increased the AUC(0-infinity) ratio of hydroxybupropion to bupropion by 63% (90% CI, 38-92%; P < 0.01). CONCLUSION: Baicalin significantly induced CYP2B6-catalyzed bupropion hydroxylation, and the effects of baicalin on other CYP2B6 substrate drugs deserve further investigation.

Herbal medicine yin zhi huang induces CYP3A4-mediated sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole.

AIM: 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-infinity) 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-infinity) 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.