Effects of fenugreek,garden cress,and black seed on theophylline pharmacokinetics in beagle dogs

Abstract

Context: Herb–drug interactions are a serious problem especially for drugs with a narrow therapeutic index, taking into consideration that herbal medicines are commonly used in various parts of the world.

Objective: The present study investigates the effect of fenugreek, garden cress, and black seed on the pharmacokinetics of theophylline in beagle dogs.

Materials and methods: Beagle dogs received theophylline (200?mg) orally and blood samples were withdrawn at different time intervals (0.33, 0.66, 1.0, 1.5, 2, 3, 4, 6, 8, 12, 24, and 30?h). After a suitable washout period, each herb was given orally at doses of 25, 7.5, and 2.5?g, twice daily for 7 d. On the eighth day, theophylline was re-administrated orally and blood samples were collected. Plasma concentrations of theophylline were determined using HPLC and pharmacokinetic parameters were calculated using a non-compartmental analysis.

Results: Treatment with fenugreek (25?g, orally) lead to a decrease in C_max and AUC_0–t of theophylline of about 28% (p?<?0.05) and 22% (p?<?0.05), respectively, with no significant changes in T_1/2λ compared with the baseline values. Garden cress caused a decrease in C_max to a lesser extent and delayed T_max of theophylline (2.10?±?0.24?h versus 3.40?±?0.74?h), while AUC_0–∞ increased by 37.44%. No significant effect was observed for the black seed treatment on theophylline disposition as measured by C_max, T_max, AUC_0–∞, and CL/F.

Discussion and conclusion: The concurrent use of fenugreek or garden cress alters theophylline pharmacokinetic behavior in an animal model. This could represent a modulation in cytochrome P450 activity, which is responsible for theophylline metabolism in beagle dogs. Further confirmation of these results in humans will warrant changes in theophylline dosing before the co-administration of such herbs.     

β1肾上腺素受体与CYP2D6基因多态性对美托洛尔抗高血压治疗的药代动力学和药效学影响

背景：美托洛尔是临床常用的抗高血压药物,它经由CYP2D6代谢。CYP2D6＊10降低CYP2D6活性,是中国人群中最为常见的多态性。β1肾上腺素受体为美托洛尔的作用靶标,Ser49Gly与Gly389Arg多态性显著改变受体功能。CYP2D6与β1肾上腺素受体遗传多态性对美托洛尔降压疗效的联合影响仍属未知。目的：发现与美托洛尔药代动力学与药效动力学相关的基因多态性位点。为提高高血压病的疗效和减少不良反应提供实验依据。方法：符合WHO/ISH高血压诊断标准的轻、中度高血压患者125例,服用美托洛尔单药治疗12周,每四周检测血压。在临床观察疗效的同时,应用PCR-RFLP方法对患者进行CYP2D6＊10与β1肾上腺素受体Ser49Gly和Gly389Arg基因型分析。同时抽取静脉血5mL,高效液相色谱-荧光检测法测定患者美托洛尔谷浓度。结果：美托洛尔谷浓度与CYP2D610基因型显著相关,并呈基因剂量效应。但高血压患者血压降低程度在CYP2D6＊1＊1、1＊10与CYP2D6＊10＊10组间无差异。Gly49携带者服用美托洛尔后收缩压与舒张压的降低显著大于Ser49Ser纯合子;与Gly389携带者相比,Arg389Arg服用美托洛尔后收缩压与舒张压的降低更为显著,表明Gly49与Arg389型受体对美托洛尔治疗有较好的敏感性。结论：CYP2D6＊10突变显著改变美托洛尔的药代动力学,但对美托洛尔的降压效果无显著性影响。β1肾上腺素受体遗传多态性与β受体阻滞药的降压敏感性有一定相关性。     

甘草酸二铵对大鼠肝微粒体细胞色素P450酶含量及活性的影响

目的研究甘草酸二铵对大鼠肝微粒体的蛋白含量、CYP450酶总量和CYP2C6、CYP2C11、CYP2D2活性的影响。方法 Wistar大鼠灌胃给予甘草酸二铵[50 mg/(kg·d)],连续7 d,测定其肝微粒体蛋白含量、CYP450蛋白含量以及CYP2C6、CYP2C11和CYP2D2活性。结果与对照组比较,甘草酸二铵给药组大鼠肝微粒体蛋白含量及肝微粒体CYP450含量差异无统计学意义(P>0.05),CYP2C6、CYP2C11酶的活性差异有统计学意义(P<0.05),CYP2D2酶活性差异无统计学意义(P>0.05)。结论甘草酸二铵可以抑制CYP2C6、CYP2C11酶的活性。     

Effects of imatinib (Glivec) on the pharmacokinetics of metoprolol, a CYP2D6 substrate, in Chinese patients with chronic myelogenous leukaemia

AIMS

To investigate the effect of imatinib on the pharmacokinetics of a CYP2D6 substrate, metoprolol, in patients with chronic myeloid leukaemia (CML). The pharmacokinetics of imatinib were also studied in these patients.

METHODS

Patients (n = 20) received a single oral dose of metoprolol 100 mg on day 1 after an overnight fast. On days 2–10, imatinib 400 mg was administered twice daily. On day 8, another 100 mg dose of metoprolol was administered 1 h after the morning dose of imatinib 400 mg. Blood samples for metoprolol and α-hydroxymetoprolol measurement were taken on study days 1 and 8, and on day 8 for imatinib.

RESULTS

Of the 20 patients enrolled, six patients (30%) were CYP2D6 intermediate metabolizers (IMs), 13 (65%) extensive metabolizers (EMs), and the CYP2D6 status in one patient was unknown. In the presence of 400 mg twice daily imatinib, the mean metoprolol AUC was increased by 17% in IMs (from 1190 to 1390 ng ml⁻¹ h), and 24% in EMs (from 660 to 818 ng ml⁻¹ h). Patients classified as CYP2D6 IMs had an approximately 1.8-fold higher plasma metoprolol exposure than those classified as EMs. The oral clearance of imatinib was 11.0 ± 2.0 l h⁻¹ and 11.8 ± 4.1 l h⁻¹ for CYP2D6 IMs and EMs, respectively.

CONCLUSIONS

Co-administration of a high dose of imatinib resulted in a small or moderate increase in metoprolol plasma exposure in all patients regardless of CYP2D6 status. The clearance of imatinib showed no difference between CYP2D6 IMs and EMs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Imatinib, a tyrosine kinase inhibitor, exhibits a competitive inhibition on the CYP450 2D6 isozyme with a K_i value of 7.5 μm. However, the clinical significance of the inhibition and its relevance to 2D6 polymorphisms have not been evaluated. The pharmacokinetics of imatinib have been well studied in Caucasians, but not in a Chinese population.
• Metoprolol, a CYP2D6 substrate, has different clearances among patients with different CYP2D6 genotypes. It is often used as a CYP2D6 probe substrate for clinical drug–drug interaction studies.

WHAT THIS STUDY ADDS

• Co-administration of imatinib at 400 mg twice daily increased the plasma AUC of metoprolol by approximately 23% in 20 Chinese patients with chronic myeloid leukaemia (CML), about 17% increase in CYP2D6 intermediate metabolizers (IMs) (n = 6), 24% in extensive metabolizers (EMs) (n = 13), and 28% for the subject with unknown 2D6 status (n = 1) suggesting that imatinib has a weak to moderate inhibition on CYP2D6 in vivo.
• The clearance of imatinib in Chinese patients with CML showed no difference between CYP2D6 IMs and EMs, and no major difference from Caucasian patients with CML based on data reported in the literature.

     

盐酸小檗碱对大鼠肝微粒体细胞色素P450酶含量及活性的影响

目的考察盐酸小檗碱对大鼠肝微粒体的蛋白含量、CYP450酶总量和主要CYP450酶亚型(CYP1A2、CYP2D6、CYP3A4和CYP2C19)活性的影响。方法以溶剂为空白对照灌胃给予盐酸小檗碱250 mg/(kg·d),连续7 d,测定其肝微粒体蛋白含量、CYP450蛋白含量以及CYP1A2、CYP2D6、CYP3A4和CYP2C19活性。结果与空白对照组比较,盐酸小檗碱给药组大鼠肝微粒体蛋白含量及肝微粒体CYP450含量无明显差异(P>0.05)。盐酸小檗碱给药后,给药组大鼠的平均CYP3A4活性是空白对照组的1/2;而两组之间CYP1A2、CYP2D6和CYP2C19的活性相当。结论盐酸小檗碱对大鼠CYP3A4活性有一定抑制作用,对CYP1A2、CYP2D6和CYP2C19的活性没有影响。     

Effects of myricetin on the bioavailability of carvedilol in rats

Context: As an inhibitor of CYP2C9, CYP2D6 and P-gp, myricetin might affect the bioavailability of carvedilol when myricetin and carvedilol are used concomitantly for the prevention or therapy of cardiovascular diseases as a combination therapy. However, the effect of myricetin on the pharmacokinetics of carvedilol has not been reported in vivo.

Objective: This study investigated the effects of myricetin on the pharmacokinetics of carvedilol after oral or intravenous administration of carvedilol in rats.

Materials and methods: Carvedilol was administered orally or intravenously with or without oral administration of myricetin to rats.

Results: The effects of myricetin on P-gp, CYP2C9 and 2D6 activity were evaluated. Myricetin inhibited CYP2C9 and CYP2D6 enzyme activity with IC50 of 13 and 57 μM, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Compared with the control group, the AUC was significantly increased by 52.0–85.1%, and the C_max was significantly increased by 93.1–133.4% in the presence of myricetin after oral administration of carvedilol. Consequently, the relative bioavailability of carvedilol was increased by 1.17- to 1.85-fold and the absolute bioavailability of carvedilol in the presence of myricetin was increased by 18.1–86.4%. T_max was significantly decreased.

Discussion and conclusion: The enhanced oral bioavailability of carvedilol may result from both inhibition of CYP2C9 or CYP2D6-mediated metabolism and P-gp-mediated efflux of carvedilol in small intestine and/or in liver by myricetin rather than reducing renal elimination. Concomitant use of myricetin or myricetin-containing dietary supplements with carvedilol will require close monitoring for potential drug interactions.     

The influence of CYP2D6 phenotype on the clinical response of nebivolol in patients with essential hypertension

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * The variability in drug metabolism has been recognized as an important factor in the occurrence of adverse effects or lack of therapeutic efficacy. * The metabolism of the third-generation beta(1)-receptor antagonist nebivolol has been shown to be highly dependent on cytochrome P450 2D6 enzymatic activity in preclinical studies. WHAT THIS STUDY ADDS: * This paper assesses the role of a cytochrome P450 2D6 gene defect on the antihypertensive response to nebivolol in a clinical setting. * Despite significant differences in drug disposition, the chronic administration of nebivolol produced similar efficacy and tolerability in hypertensive patients either characterized as poor or extensive metabolizers of the drug. * The study offers insight into the relative contribution of nebivolol enantiomers in systemic blood pressure control. AIMS: Nebivolol is a beta(1)-adrenergic receptor antagonist with vasodilating properties used in the treatment of hypertension. It is administered as a racemic mixture (D- and L-nebivolol) and is highly metabolized by the cytochrome P-450 2D6 (CYP2D6). The purpose of this study was to determine the role of CYP2D6 phenotypes on the efficacy and tolerability of nebivolol during chronic administration to patients with essential hypertension. METHODS: Two hundred and eighteen patients were genotyped and phenotyped for CYP2D6 activity, allowing to find and match 14 poor metabolizers (PMs) with 23 extensive metabolizers (EMs). Patients took rac-nebivolol 5 mg daily for 12 weeks. Blood pressure (BP), heart rate, adverse events, plasma levels of the two enantiomers D- and L-nebivolol and their corresponding hydroxymetabolites were assessed. RESULTS: The metabolic disposition of nebivolol was enantioselective and highly influenced by CYP2D6 phenotypes. Mean steady-state plasma concentrations of D- and L-nebivolol were 10- and 15-fold greater in PMs than in EMs, respectively (P < 0.0001). Despite these differences in the pharmacokinetics of nebivolol, EMs and PMs displayed similar BP responses. Mean reductions in sitting systolic and diastolic BPs were -11/-10 +/- 9/4 mmHg in EMs and -11/-9 +/- 10/5 mmHg in PMs. Side-effects were mild to moderate and not different between groups. CONCLUSION: Polymorphisms in the gene encoding CYP2D6 significantly influenced the metabolism of nebivolol, but not its antihypertensive efficacy and tolerability. The similar clinical response between EMs and PMs could be explained by the contribution of active hydroxylated metabolites of nebivolol to its antihypertensive actions in EMs.     

Effects of CYP2D6 status on harmaline metabolism, pharmacokinetics and pharmacodynamics, and a pharmacogenetics-based pharmacokinetic model

Harmaline is a β-carboline alkaloid showing neuroprotective and neurotoxic properties. Our recent studies have revealed an important role for cytochrome P450 2D6 (CYP2D6) in harmaline O-demethylation. This study, therefore, aimed to delineate the effects of CYP2D6 phenotype/genotype on harmaline metabolism, pharmacokinetics (PK) and pharmacodynamics (PD), and to develop a pharmacogenetics mechanism-based compartmental PK model. In vitro kinetic studies on metabolite formation in human CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) hepatocytes indicated that harmaline O-demethylase activity (V_max/K_m) was about 9-fold higher in EM hepatocytes. Substrate depletion showed mono-exponential decay trait, and estimated in vitro harmaline clearance (CL_int, μL/min/10⁶ cells) was significantly lower in PM hepatocytes (28.5) than EM hepatocytes (71.1). In vivo studies in CYP2D6-humanized and wild-type mouse models showed that wild-type mice were subjected to higher and longer exposure to harmaline (5 and 15 mg/kg; i.v. and i.p.), and more severe hypothermic responses. The PK/PD data were nicely described by our pharmacogenetics-based PK model involving the clearance of drug by CYP2D6 (CL_CYP2D6) and other mechanisms (CL_other), and an indirect response PD model, respectively. Wild-type mice were also more sensitive to harmaline in marble-burying tests, as manifested by significantly lower ED₅₀ and steeper Hill slope. These findings suggest that distinct CYP2D6 status may cause considerable variations in harmaline metabolism, PK and PD. In addition, the pharmacogenetics-based PK model may be extended to define PK difference caused by other polymorphic drug-metabolizing enzyme in different populations.     

Effects of DRD2 and CYP2D6 genotypes on delta EEG power response to aripiprazole in healthy male volunteers: a preliminary study

The aim of the present study was to evaluate the effects of polymorphisms in dopamine D2 receptor (DRD2) and cytochrome P450 (CYP) 2D6 genes on delta EEG power response to aripiprazole in healthy male volunteers. Seventeen volunteers were recruited according to the DRD2 Taq1A genotype, and separated into the following groups: homozygous wild-type (A2/A2, n = 7), heterozygous (A2/A1, n = 5) and homozygous variant-type (A1/A1, n = 5) groups. After enrollment in this study, they were genotyped for CYP2D6. The volunteers received single 10 mg oral doses of aripiprazole, in accordance with an open-label parallel group study design. Plasma levels of aripiprazole and its metabolite were determined and EEGs were obtained simultaneously. The pharmacodynamic parameter was absolute delta power in the Cz channel. The changes of delta power were not different according to DRD2 Taq1A genotypes. As to the CYP2D6 allele, the subjects had the following CYP2D6 genotypes: *10/*10 (n = 4), *1/*10 (n = 5), *1/*5 (n = 2), *1/*1 (n = 3), *2/*41 (n = 1), *2/*2 (n = 1), *2N/*10 (n = 1). Subjects exhibiting the *1/*5 and *1/*10 genotypes showed a trend toward high area under the plasma aripiprazole concentration-time curve (AUC), which was linearly related to area under the EEG response-time curve (AUEC). Our results demonstrate a need for further evaluation of the CYP2D6 genotypic effect on the pharmacodynamics of aripiprazole.     

The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver

AIMS: To investigate in a large panel of 50 human liver samples the contribution of CYP2C9, CYP2D6, and CYP3A4 to the overall formation of the potent antioestrogen Z-4-hydroxy-tamoxifen, and how various genotypes affect its formation from tamoxifen. METHODS: The formation of Z-4-hydroxy-tamoxifen from 10 microm tamoxifen was studied in human liver microsomes (n=50), characterized for CYP2B6, CYP2C9, CYP2D6 and CYP3A4 expression, and CYP2B6, CYP2C9 and CYP2D6 genotype. The effect of chemical and monoclonal antibody inhibitors, and the formation in supersomes expressing recombinant CYP isoforms was also investigated. Z-4-hydroxy-tamoxifen was quantified using LC-MS analysis. RESULTS: Z-4-hydroxy-tamoxifen was formed by supersomes expressing CYP2B6, CYP2C9, CYP2C19 and CYP2D6, but not CYP3A4. In agreement with these data, the mean formation of Z-4-hydroxy-tamoxifen was inhibited 49% by sulphaphenazole (P=0.001), 38% by quinidine (P<0.05) and 13% by monoclonal antibody against CYP2B6 (MAB-2B6, P<0.05). Furthermore, Z-4-hydroxy-tamoxifen formation significantly correlated with both CYP2C9 expression (r(s)=0.256, P<0.05) and CYP2D6 expression (r(s)=0.309, P<0.05). Genotypes of CYP2D6, CYP2B6 and CYP2C9 had an effect on metabolite formation in such a way that samples with two nonfunctional CYP2D6, or two variant CYP2C9 or CYP2B6 alleles, showed lower enzyme activity compared with those with two functional or wild-type alleles, (5.0 vs 9.9 pmol mg(-1) protein min(-1), P=0.046, 5.1 vs 9.9 pmol mg(-1) protein min(-1), P=0.053, and 6.8 vs 9.4 pmol mg(-1) protein min(-1), P=0.054, respectively). CYP2D6 and CYP2C9 contribute on average 45 and 46%, respectively, to the overall formation of Z-4-hydroxy-tamoxifen. CONCLUSIONS: CYP2B6, CYP2C9 and CYP2D6 genotypes all affected Z-4-hydroxy-tamoxifen formation and can predict individual ability to catalyse this reaction.     

Effects of CYP2C11 gene knockout on the pharmacokinetics and pharmacodynamics of warfarin in rats

1. CYP2C11 is the most abundant isoform of cytochrome P450s (CYPs) in male rats and is considered the main enzyme for warfarin metabolism.

2. To further access the in vivo function of CYP2C11 in warfarin metabolism and efficacy, a CYP2C11-null rat model was used to study warfarin metabolism with both in vitro and in vivo approaches. Prothrombin time (PT) of warfarin was also determined.

3. The maximum rate of metabolism (V_max) and intrinsic clearance (CL_int) of liver microsomes from CYP2C11-null males were reduced by 37 and 64%, respectively, compared to those in Sprague Dawley (S-D) rats. The K_m of liver microsomes from CYP2C11-null males was increased by 73% compared to that of S-D rats. The time to reach the maximum plasma concentration (T_max) of warfarin in CYP2C11-null males was significantly delayed compared to that in S-D males, and the CL rate was also reduced. The PT of CYP2C11-null rats was moderately longer than that of S-D rats.

4. In conclusion, the clearance rate of warfarin was mildly decreased and its anticoagulant effect was moderately increased in male rats following CYP2C11 gene knockout. CYP2C11 played a certain role in the clearance and efficacy of warfarin, while it did not seem to be essential.     

Effects of strong CYP2D6 and 3A4 inhibitors, paroxetine and ketoconazole, on the pharmacokinetics and cardiovascular safety of tamsulosin

AIMTo determine the effect of the strong CYP2D6 inhibitor paroxetine and strong CYP3A4 inhibitor ketoconazole on the pharmacokinetics and safety (orthostatic challenge) of tamsulosin.METHODSTwo open-label, randomized, two-way crossover studies were conducted in healthy male volunteers (extensive CYP2D6 metabolizers).RESULTSCo-administration of multiple oral doses of 20 mg paroxetine once daily with a single oral dose of the 0.4 mg tamsulosin HCl capsule increased the adjusted geometric mean (gMean) values of C_max and AUC(0,∞) of tamsulosin by factors of 1.34 (90% CI 1.21, 1.49) and 1.64 (90% CI 1.44, 1.85), respectively, and increased the terminal half-life (t_1/2) of tamsulosin HCl from 11.4 h to 15.3 h. Co-administration of multiple oral doses of 400 mg ketoconazole once dailywith a single oral dose of the 0.4 mg tamsulosin increased the gMean values of C_max and AUC(0,∞) of tamsulosin by a factor of 2.20 (90% CI 1.96, 2.45) and 2.80 (90% CI 2.56, 3.07), respectively. The terminal half-life was slightly increased from 10.5 h to 11.8 h. These pharmacokinetic changes were not accompanied by clinically significant alterations of haemodynamic responses during orthostatic stress testing.CONCLUSIONThe exposure to tamsulosin is increased upon co-administration of strong CYP2D6 inhibitors and even more so of strong 3A4 inhibitors, but neither PK alteration was accompanied by clinically significant haemodynamic changes during orthostatic stress testing.     

Effect of smoking and CYP2D6 polymorphisms on the extent of fluvoxamine–alprazolam interaction in patients with psychosomatic disease

Purpose  Fluvoxamine (FVX) is metabolized by cytochrome P450 (CYP) 2D6 and CYP1A2 and inhibits CYP3A4. The aim of this study was to investigate the factors responsible for interindividual variability in the extent of interaction between FVX and alprazolam (ALP). Methods  Blood samples were taken from 49 depressive patients to determine plasma concentration of FVX, ALP or both. Twenty-four samples were taken during the FVX-alone period, 21 samples during the ALP-alone period and 30 samples during the FVX-ALP period. Subjects were also genotyped for CYP2D6. Results  The concentration-to-dose (C/D) ratio of ALP during the FVX-treatment period was significantly higher than that during the ALP-alone period. The CYP2D6 genotype affected neither the C/D ratios of FVX nor the extent of interaction. The mean C/D ratio of FVX in smokers was reduced by more than 30% in comparison with that in non-smokers. The mean C/D ratio of ALP in non-smokers was increased by FVX, while that in smokers was unchanged. Conclusions  The extent of interaction between FVX and ALP may be affected by smoking, which alters the C/D ratio of FVX. Therefore, when FVX and ALP are concomitantly administered, it should be noted that non-smokers may exhibit greater drug interaction than smokers.     

Influence of genetic polymorphisms and habitual caffeine intake on the changes in blood pressure,pulse rate,and calculation speed after caffeine intake: A prospective,double blind,randomized trial in healthy volunteers

The aim of this study was to investigate the contribution of gene polymorphisms, in combination with habitual caffeine consumption, to the effect of caffeine intake on hemodynamic and psychoactive parameters. A double-blind, prospective study was conducted with 201 healthy volunteers randomly allocated 2:1 to the caffeinated group (150 mL decaffeinated coffee with additional 200 mg caffeine) or decaffeinated group (150 mL decaffeinated coffee). We measured the changes in blood pressure (BP) and calculation speed upon coffee intake, stratifying with gene polymorphisms, e.g., those in adenosine A_2A receptor (ADORA2A) and cytochrome P450 (CYP) 1A2, and daily caffeine consumption (≤90 mg/day and >90 mg/day). Overall, caffeine intake independently increased BP and calculation speed (p-values < 0.05), irrespective of the polymorphisms. In stratified analysis, a statistical significance within the caffeinated group was observed for the change in systolic BP in the stratum of CYP1A2 polymorphism with daily caffeine consumption ≤90 mg/day: change in systolic BP in the CYP1A2 rs762551 CC group (mean ± SD = 11.8 ± 5.9) was higher than that in the AA/CA group (4.1 ± 5.5). Gene polymorphisms may limitedly modify the effect of caffeine intake on hemodynamic parameters in combination with habitual caffeine consumption.     

Effects of cysteine on the pharmacokinetics of intravenous chlorzoxazone in rats with protein-calorie malnutrition

The effects of cysteine on the pharmacokinetics of chlorzoxazone (CZX) and one of its metabolites, 6-hydroxychlorzoxazone (OH-CZX), were investigated after intravenous administration of CZX, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily during the fourth week). In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity (AUC) of OH-CZX (436 compared with 972 microgmin/ml) and the percentages of intravenous dose of CZX excreted in 8-h urine as OH-CZX (20.2 compared with 38.5%) were significantly smaller than those in control rats. The above data indicated that the formation of OH-CZX from CZX decreased significantly in rats with PCM due to a significant decrease in chlorzoxazone-6-hydroxylase activity (328 compared with 895 pmol/min/mg protein) in the rats. The results were expected since in rats with PCM, hepatic CYP2E1 expression and its mRNA levels decreased significantly as compared to control, and CZX was metabolized to OH-CZX primarily by CYP2E1 in rats. By cysteine supplementation (rats with PCMC), some pharmacokinetic parameters restored fully (hepatic microsomal chlorzoxazone 6-hydroxylation activity based on both mg protein and nmol CYP450) or partially (total body clearance and apparent volume of distribution at steady state of CZX, and AUC, terminal half-life and 8-h urinary excretion of OH-CZX) to control levels.     

The effect of paroxetine on the pharmacokinetics,safety, and tolerability of ramosetron in healthy subjects

Objective The aim of our study was to investigate the effects of multiple doses of paroxetine on the pharmacokinetics, safety, and tolerability of a single oral 10-μg dose of ramosetron. Methods This was an open, one-sequence crossover design study. On day 1, healthy male and female subjects were administered a single dose of 10 μg ramosetron. On the morning of day 3, the subjects were administered paroxetine to reach steady state, which consisted of morning doses of 20 mg on days 3–12. The dose on day 11 was administered in combination with a single dose of 10 μg ramosetron. Results In subjects genotyped as extensive CYP2D6 metabolizers, coadministration of paroxetine with ramosetron resulted in an increase in area under the curve from 0 to infinity (AUC_0-inf) and the peak concentration (C_max) of ramosetron by 1.14-fold (90% confidence interval (CI): 1.07–1.22) and by 1.06-fold (90% CI: 1.00–1.11), respectively. Conclusions It can be concluded that the single-dose pharmacokinetic profile of ramosetron 10 μg is not affected to a clinically relevant degree by paroxetine 20 mg once daily administered for 10 days.     

Effect of St John's wort on the activities of CYP1A2, CYP3A4, CYP2D6, N-acetyltransferase 2, and xanthine oxidase in healthy males and females

AIMS: To investigate the influence of St. John's wort (SJW) on CYP3A4, CYP1A2, CYP2D6, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activities in healthy males and females. METHODS: Eight males and eight females were treated with SJW extract (3 x 300 mg day(-1)) for 14 days. Assessment of CYP1A2, NAT2, XO, CYP2D6, and CYP3A4 activities was performed before and at the end of the study period, using caffeine, dextromethorphan, and endogenous cortisol as probes. The corresponding metabolic ratios measured were 17MX/137MX in saliva and (AFMU+1MX+1MU)/17MU in urine for CYP1A2, AFMU/1MX for NAT2, 1MU/1MX for XO, DOR/DMO for CYP2D6, 3MM/DMO and 6OHC/C for CYP3A4, all determined in urine. RESULTS: The ratios of the treatment to baseline values for CYP3A4 using cortisol as the probe were 1.5 [95% confidence interval (CI) 1.3, 1.9] for males, and 1.9 (1.1, 3.0) for females. The corresponding ratios using dextromethorphan as the probe for CYP2D6 were 0.9 (95% CI 0.5, 2.1) for males and 1.9 (1.3, 3.2) for females. For CYP1A2, a significant increase in the metabolic ratios was found only for females (ratio of values 1.2; 95% CI 1.1, 1.4). No influence of SJW on CYP2D6, NAT2, and XO activities was observed. CONCLUSIONS: An induction of CYP3A4 by SJW was confirmed. CYP1A2 appears to be induced by SJW only in females. The activities of CYP2D6, NAT2, and XO were not affected by SJW.