Telmisartan increases systemic exposure to rosuvastatin after single and multiple doses, and in vitro studies show telmisartan inhibits ABCG2-mediated transport of rosuvastatin.

PURPOSE: The ATP-binding cassette transporter G2 (ABCG2) plays an important role in the disposition of rosuvastatin. Telmisartan, a selective angiotension-II type 1 (AT1) receptor blocker, inhibits the transport capacity of ABCG2, which may result in drug interactions. This study investigated the pharmacokinetic interaction between rosuvastatin and telmisartan and the potential mechanism. METHODS: In this two-phase fixed-order design study, healthy subjects received single doses of 10 mg rosuvastatin at baseline and after telmisartan 40 mg daily for 14 days. Patients with hyperlipidaemia who had been taking rosuvastatin 10 mg daily for at least 4 weeks were given telmisartan 40 mg daily for 14 days together with rosuvastatin. Plasma concentrations of rosuvastatin were measured over 24 h before and after telmisartan administration. In vitro experiments using a bidirectional transport assay were performed to investigate the involvement of ABCG2 in the interaction. RESULTS: Co-administration of telmisartan significantly increased the maximum plasma concentration (C max) and the area under the plasma concentration-time curve (AUC) of rosuvastatin by 71 and 26 %, respectively. The T max values were reduced after administration of telmisartan. There was no significant difference in the interaction of rosuvastatin with telmisartan between healthy volunteers and patients receiving long-term rosuvastatin therapy or among subjects with the different ABCG2 421 C>A genotypes. The in vitro experiment demonstrated that telmisartan inhibited ABCG2-mediated efflux of rosuvastatin. CONCLUSION: This study demonstrated that telmisartan significantly increased the systemic exposure to rosuvastatin after single and multiple doses.

Effect of common polymorphisms of the farnesoid X receptor and bile acid transporters on the pharmacokinetics of ursodeoxycholic acid.

Ursodeoxycholic acid (UDCA), a natural, dihydroxy bile acid, promotes gallstone dissolution and has been attributed with several other beneficial effects. The farnesoid X receptor (FXR) may influence the pharmacokinetics of UDCA by modulating the expression of bile acid transporters. This exploratory study examined whether common functional polymorphisms in FXR and in bile acid transporter genes affect the pharmacokinetics of exogenous UDCA. Polymorphisms in genes for transporters involved in bile acid transport, solute carrier organic anion 1B1 (SLCO1B1) 388A>G and 521T>C, solute carrier 10A1 (SLC10A1) 800 C>T and ATP-binding cassette B11 (ABCB11) 1331T>C, and the FXR -1G>T polymorphism were genotyped in 26 male Chinese subjects who ingested single oral 500-mg doses of UDCA. Plasma concentrations of UDCA and its major conjugate metabolite glycoursodeoxycholic acid (GUDCA) were determined. The mean systemic exposure of UDCA was higher in the five subjects with one copy of the FXR -1G>T variant allele than in those homozygous for the wild-type allele (n = 21) (AUC0-24 h : 38.5 ± 28.2 vs. 20.9 ± 8.0 µg h/mL, P = 0.021), but this difference appeared mainly due to one outlier with the -1GT genotype and elevated baseline and post-treatment UDCA concentrations. After excluding the outlier, body weight was the only factor associated with plasma concentrations of UDCA and there were no significant associations with the other polymorphisms examined. None of the polymorphisms affected the pharmacokinetics of GUDCA. This study showed that the common polymorphisms in bile acid transporters had no significant effect on the pharmacokinetics of exogenous UDCA but an effect of the FXR polymorphism cannot be excluded.

Study of potential cardioprotective effects of Ganoderma lucidum (Lingzhi): results of a controlled human intervention trial.

Previous studies have suggested that Lingzhi (Ganoderma lucidum) has antioxidant effects and possibly beneficial effects on blood pressure, plasma lipids and glucose, but these have not been confirmed in subjects with mild hypertension or hyperlipidaemia. The objective of the present study was to assess the cardiovascular, metabolic, antioxidant and immunomodulatory responses to therapy with Lingzhi in patients with borderline elevations of blood pressure and/or cholesterol in a controlled cross-over trial. A total of twenty-six patients received 1·44 g Lingzhi daily or matching placebo for 12 weeks in a randomised, double-blind, cross-over study with placebo-controlled run-in and cross-over periods. Body weight, blood pressure, metabolic parameters, urine catecholamines and cortisol, antioxidant status and lymphocyte subsets were measured after each period. Lingzhi was well tolerated and data from twenty-three evaluable subjects showed no changes in BMI or blood pressure when treated with Lingzhi or placebo. Plasma insulin and homeostasis model assessment-insulin resistance were lower after treatment with Lingzhi than after placebo. TAG decreased and HDL-cholesterol increased with Lingzhi but not with placebo in the first treatment period, but significant carry-over effects prevented complete analysis of these parameters. Urine catecholamines and cortisol, plasma antioxidant status and blood lymphocyte subsets showed no significant differences across treatments. Results indicate that Lingzhi might have mild antidiabetic effects and potentially improve the dyslipidaemia of diabetes, as shown previously in some animal studies. Further studies are desirable in patients with hyperglycaemia.

Effects of CYP2D6*10, CYP3A5*3, CYP1A2*1F, and ABCB1 C3435T polymorphisms on the pharmacokinetics of flecainide in healthy Chinese subjects.

BACKGROUND: Although flecainide is thought to be meta-bolized predominantly by cytochrome P450 (CYP) 2D6, it shows pharmacokinetic interactions with drugs, such as verapamil and digoxin, which may suggest other CYP pathways or ATP-binding cassette (ABC) transporters might be involved. This study evaluated effects of common polymorphisms in Chinese in CYP2D6, CYP3A5, CYP1A2, and ABCB1 on flecainide pharmacokinetics. METHODS: Single oral 100-mg doses of flecainide were given to 15 healthy male Chinese subjects who were genotyped for the CYP2D6*2, *5, *10, CYP3A5*3, CYP1A2*1F and ABCB1 C1236T, G2677T/A, and C3435T polymorphisms. RESULTS: There was no significant difference in the pharmacokinetics of flecainide among CYP2D6 (mainly involving *10) genotypes. The CYP3A5*3/*3 subjects (n=8) had a 26% higher systemic exposure (AUC0-∞) and 17% lower apparent oral clearance of flecainide than the combined group of CYP3A5*1/*1 (n=6) and CYP3A5*1/*3 (n=1) subjects (p<0.05). Subjects homozygous for CYP1A2*1F tended to have lower systemic exposure and increased clearance of flecainide compared to those with CYP1A2*1A/1F in subjects with at least one CYP2D6 variant allele. CONCLUSIONS: The disposition of flecainide appeared to be influenced by the CYP3A5*3 and possibly the CYP1A2*1F polymorphisms, particularly in subjects with CYP2D6 variant alleles.

Factors Associated with Aspirin Resistance in Hong Kong Chinese Patients with Stable Coronary Heart Disease Using the Multiplate® Analyzer and Serum Thromboxane B2.

Introduction: Aspirin resistance may be associated with various conditions. We measured serum thromboxane B2 (TXB2) and platelet function using the Multiplate® Analyzer with arachidonic acid (ASPI) in patients on long term aspirin therapy to identify aspirin resistance and associated factors. Materials and Methods: Chinese patients with stable coronary heart disease had samples for serum TXB2 and ASPI measurement taken before and 1 h after taking a morning dose of 80 mg aspirin. Results: In 266 patients with mean age 66.6 ± 10.7 years, 17% were female and 55% were current or previous smokers. TXB2 and ASPI measurements were significantly higher before the dose than at 1 h post dose, with 46% of subjects having high ASPI values (AUC > 300 AU*min) pre dose compared with 27% at 1 h post dose. TXB2 and ASPI measures of platelet aggregation showed weak correlations, which were only significant before the dose (r = 0.219, p = 0.001). Increased ASPI measurements were associated with white blood cell (WBC) count, haematocrit, platelet count and heart rate at 24 h post dose but only with WBC count, smoking history and heart rate at 1 h post dose. Diabetes was not associated with reduced platelet response to aspirin. The WBC count associated with aspirin resistance was over 6.55 × 109/L by receiver operating characteristic analysis. Conclusions: The antiplatelet response to aspirin was reduced in a large proportion of patients. Patients with higher WBC count within the normal range appear to be at increased risk of aspirin resistance. Higher or more frequent doses of aspirin may be needed in many patients.

The effects of increasing doses of noradrenaline on systemic and renal circulations in acute bacteraemic dogs.

OBJECTIVE: To determine the dose-response effects of noradrenaline on the systemic and renal circulations during septic shock. DESIGN AND SETTING: Prospective controlled experiment in a university animal laboratory. SUBJECTS: Eight anaesthetized dogs. INTERVENTIONS: Transonic flow probes were surgically placed on the aorta via a left lateral thoracotomy and on the left renal artery. Blood pressure was measured from the femoral artery. Acute bacteraemia shock was induced by injecting Escherichia coli bacteria intravenously. Increasing doses of noradrenaline (0.1, 0.2, 0.3, 0.4, 0.5 microg kg(-1) min(-1)) were infused intravenously for 30 min at 30-min intervals. The model was first validated in four dogs. MEASUREMENTS AND RESULTS: Mean arterial pressure, central venous pressure, cardiac output, and renal blood flow were measured. Systemic vascular resistance was derived. Induction of bacteraemia decreased mean arterial pressure, central venous pressure and systemic vascular resistance. Cardiac output slightly increased. Noradrenaline produced linear dose-dependent increases in both mean arterial pressure and systemic vascular resistance. The response was attenuated during bacteraemia. Under non-bacteraemic conditions the maximum dose of noradrenaline reduced the renal blood flow from 12+/-1 to 10+/-1 ml kg(-1) min(-1). Bacteraemia further reduced renal blood flow to 7+/-1 ml kg(-1) min(-1), which was partly restored by the maximum dose of noradrenaline to 11+/-3 ml kg(-1) min(-1). CONCLUSIONS: Noradrenaline can restore mean arterial pressure in bacteraemic shock and increases in mean arterial pressure are dose-dependent. The noradrenaline response is attenuated by bacteraemic shock. In bacteraemic shock noradrenaline also improves renal perfusion, as perfusion pressure increases. However, renal blood flow is not fully restored, suggesting that an element of impairment of renal blood flow exists due to the bacteraemia or noradrenaline.

Pharmacokinetic properties of single-dose lamivudine/adefovir dipivoxil fixed-dose combination in healthy Chinese male volunteers.

BACKGROUND: Both lamivudine and adefovir dipivoxil are approved for the treatment of chronic hepatitis B (CHB) and have established safety profiles. A fixed-dose combination (FDC) formulation of lamivudine/adefovir dipivoxil for the treatment of CHB may provide dosing convenience and improve adherence. OBJECTIVE: This study compared the pharmacokinetic profiles of an FDC capsule containing lamivudine/adefovir dipivoxil 100/10 mg and conventional lamivudine 100-mg + adefovir dipivoxil 10-mg tablets to determine bioequivalence. METHODS: This randomized, open-label, single-dose, 2-period crossover study was conducted in healthy male Chinese subjects. The study included a screening visit, 2 treatment sessions, and a follow-up visit. Subjects who met the inclusion/exclusion criteria were assigned to receive, in randomized order, 1 FDC capsule or 1 tablet each of lamivudine and adefovir dipivoxil. After a 7- to 10-day washout period, alternate treatment was given to the subjects during the second treatment session. Blood samples were collected immediately before and after dosing for 48 hours for plasma drug concentration measurement. Data on adverse events (AEs) were collected from the start of dosing until the follow-up visit. Tolerability assessments included physical examinations with vital sign measurements and clinical laboratory evaluations throughout the study. RESULTS: Forty subjects were enrolled into the study (mean age, 22.4 years [range, 19-28 years]; weight, 63.8 kg [range, 54-78 kg]). The pharmacokinetic profiles of lamivudine and adefovir were similar between the FDC and reference formulations. The geometric mean ratios (GMRs) for lamivudine C(max) and AUC(0-last) were 1.02 (90% CI, 0.92-1.12) and 0.99 (90% CI, 0.95-1.04), respectively; adefovir, 0.94 (90% CI, 0.89-0.99) and 0.95 (90% CI, 0.91-1.00). A limited number of mild AEs were reported, with no clinically significant changes in vital signs or laboratory results. CONCLUSIONS: The FDC capsule was bioequivalent to the concurrent administration of lamivudine + adefovir dipivoxil tablets based on the 90% CIs of the GMRs for C(max), AUC(0-∞), AUC(0-last), and t12 (all were between 0.80 and 1.25). Both treatments were well-tolerated.

Evaluation of impedance based indices of cardiac contractility in dogs.

OBJECTIVE: Cardiac function can be monitored simply and safely by the impedance method. A number of parameters that reflect cardiac contractility can be derived from the impedance waveform. These include the systolic time ratio (STR), the index of contracticity (IC), the acceleration index (ACI) and the Heather index. This study evaluates their reliability. METHODS: In sixteen anaesthetized dogs an ultrasonic flow probe was placed on the ascending aorta using a left thoracotomy approach and catheter placed in the femoral artery to measure blood pressure. This allowed the reference measurement of cardiac contractility from blood flow (dF/dt(max)) and pressure (dP/dt(max)). Comparative 1-minute impedance based measurements were made by a RheoCardioMonitor (ACMA, Singapore), whilst contractility was increased 2 to 6 fold, over 113 (52 to 212) minutes, using dopamine and adrenaline infusions. The association between the reference and impedance measurements was determined by correlation. The correlation coefficients (r) were compared using paired t-tests. Results are presented as mean +/- SD. RESULTS: The ACI (r = 0.76 +/- 0.13) and Heather index (r = 0.74 +/- 0.14) were more closely associated with the reference measurement (dF/dt(max)) than IC (r = 0.65 +/- 0.23) (p < 0.05) and STR (r = 0.33 +/- 24) (p < 0.01). Results for ACI and the Heather index were similar. STR was unrelated to the reference method in 10 out of 16 experiments. Correlation was better when using flow probe data (dF/ dt(max)) than arterial pressure data (dP/dt(max)) (p < 0.05). CONCLUSIONS: ACI and the Heather index were the most reliable impedance derived indices of cardiac contractility.