Plasma and brain pharmacokinetics of ganoderic acid A in rats determined by a developed UFLC-MS/MS method.

Ganoderic acid A (GAA), an active triterpenoid of the traditional Chinese herbal medicine Lingzhi, has been reported to exhibit antinociceptive, antioxidative, and anti-cancer activities. The present study aims to establish a sensitive and rapid UPLC-MS/MS method for studying the plasma and brain pharmacokinetics of GAA in rats. The analytes were separated on a C18 column eluted with a gradient mobile phase consisting of acetonitrile and 0.1% aqueous formic acid at 0.3mL/min. The eluate was monitored by a mass detector using an MRM (m/z, 515.3-285.1) model in negative electrospray ionization. The calibration curve showed good linearity (r2>0.99), with limits of detection and quantification of 0.25 and 2.00 nmol/L, respectively. The intra- and inter-day precision and accuracy were less than 9.99% and ranged from 97.45% to 114.62%, respectively. The extraction recovery from plasma was between 92.89% and 98.87%. GAA was found to be stable in treated samples at room temperature (22°C) for 12h and in plasma at -20°C for 7d. The developed method was successfully applied to a pharmacokinetic study of GAA in rats. GAA could be rapidly absorbed into the circulation (Tmax, 0.15h) and eliminated relatively slowly (t1/2, 2.46h) after orally dosing, and could also be detected in the brain lateral ventricle (Tmax, 0.25h and t1/2, 1.40h) after intravenously dosing. The absolute oral bioavailability and brain permeability of GAA were estimated to be 8.68% and 2.96%, respectively.

High-dose supplementation with natural α-tocopherol does neither alter the pharmacodynamics of atorvastatin nor its phase I metabolism in guinea pigs.

It has been hypothesized in the literature that intake of high-dosage vitamin E supplements might alter the expression of cytochrome P(450) enzymes (CYP), particularly CYP3A4, which may lead to adverse nutrient-drug interactions. Because previously published studies reported conflicting findings, we investigated the pharmacodynamics of the lipid-lowering drug atorvastatin (ATV), a CYP3A4 substrate, in response to high-dose α-tocopherol (αT) feeding and determined protein expression and activities of relevant CYP. Groups of ten female Dunkin-Hartley guinea pigs were fed a control (5% fat) or a high-fat control diet (HFC; 21% fat, 0.15% cholesterol) or the HFC diet fortified with αT (250 mg/kg diet), ATV (300 mg/kg diet) or both ATV+αT for 6 weeks. Relative to control, HFC animals had increased serum cholesterol concentrations, which were significantly reduced by ATV. High-dose αT feeding in combination with ATV (ATV+αT), albeit not αT feeding alone (αT), significantly lowered serum cholesterol relative to HFC, but did not alter the cholesterol-lowering activity of the drug compared to the ATV treated guinea pigs. Protein expression of CYP3A4, CYP4F2, CYP20A1 and OATP C was similar in all groups. Accordingly, no differences in plasma concentrations of phase I metabolites of ATV were observed between the ATV and ATV+αT groups. In conclusion, feeding guinea pigs high-doses of αT for 6 weeks did neither alter the hepatic expression of CYP, nor the pharmacodynamics and metabolism of ATV. High-dose αT intake is thus unlikely to change the efficacy of drugs metabolized by CYP enzymes, particularly by CYP3A4.

Effects of Ginkgo biloba extracts on pharmacokinetics and efficacy of atorvastatin based on plasma indices.

Ginkgo biloba extract (GBE) is one of the most widely used herbal medicines in the world. It is often administered in combination with statins to treat diseases, especially some nervous system disorders. We aimed to investigate the influences of GBE on pharmacokinetics and efficacy of atorvastatin, which are currently unclear. Sixteen volunteers received a single oral dose of 40 mg atorvastatin, followed by a wash-out period of at least 5 days. Then the volunteers took 360 mg GBE daily for 14 days, followed by a single dose of 40 mg atorvastatin. Serial blood samples obtained over a period of 48 h after atorvastatin ingestion were subjected to determination of atorvastatin plasma concentrations and markers of cholesterol synthesis (lathosterol) and cholesterol absorption (sitosterol). With GBE administration, AUC0₋48, AUC(0-∞) and C(max) of atorvastatin were reduced by 14.27% (p = 0.005), 10.00% (p = 0.03) and 28.93% (p = 0.002), respectively; Vd/F and CL/F of atorvastatin were increased by 31.95% (p = 0.017) and 6.48% (p = 0.044). After 14 days of treatment, GBE has no significant effects on cholesterol-lowering efficacy of atorvastatin. This study suggests that GBE slightly decreases the plasma atorvastatin concentrations, but has no meaningful effect on the cholesterol-lowering efficacy of atorvastatin.

The effect of the newly developed angiotensin receptor II antagonist fimasartan on the pharmacokinetics of atorvastatin in relation to OATP1B1 in healthy male volunteers.

OBJECTIVE: Interactions between coadministered drugs may unfavorably affect pharmacokinetics. This study evaluated whether fimasartan, an angiotensin receptor II antagonist, affected the pharmacokinetics of atorvastatin. METHODS: A randomized, open-label, 2-period, 2-sequence, crossover, multiple-dosing study was conducted with 24 healthy male volunteers. Twelve subjects received 80-mg atorvastatin once daily for 7 days; later, they received 80-mg atorvastatin with 240-mg fimasartan for 7 days. Twelve other subjects received the same drugs in the opposite sequence. Blood samples were collected scheduled intervals for 24 hours after the last dosing to determine plasma concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxy atorvastatin acid, and 2-hydroxy atorvastatin lactone. RESULTS: Compared with atorvastatin alone, coadministration of fimasartan and atorvastatin increased the atorvastatin acid mean (95% confidence interval) maximum concentration (Cmax,ss) by 1.89-fold (1.49-2.39) and the area under the concentration curve (AUCτ,ss) by 1.19-fold (0.96-1.48). Fimasartan also increased the mean 2-hydroxy atorvastatin acid Cmax,ss and AUCτ,ss by 2.45-fold (1.80-3.35) and 1.42-fold (1.09-1.85), respectively. The Cmax,ss and AUCτ,ss of the lactone forms of atorvastatin showed smaller changes than those observed for the acidic forms. CONCLUSION: We showed that fimasartan raised plasma atorvastatin concentrations. In vitro tests suggested that this effect may have been mediated by fimasartan inhibition of organic anion-transporting polypeptide 1B1.

Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence.

The objective of this study was to determine vitamin D supplementation effects on concentrations of atorvastatin and cholesterol in patients. Sixteen patients (8 men, 8 women; 10 Caucasians, 4 African Americans, 1 Hispanic, 1 Asian), aged 63 +/- 11 years (mean +/- SD, weight 92 +/- 31 kg) on atorvastatin (45 +/- 33 mg/day) were studied with and without supplemental vitamin D (800 IU/day for 6 weeks). Levels of vitamin D (1,25-dihydroxy(OH) and 25 OH-metabolites), atorvastatin (parent, OH-acid metabolites, lactone, and lactone metabolites), and cholesterol (total, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol) were determined at 0.5, 3, and 10 h after dosing. Vitamin D supplementation increased vitamin D-25-OH metabolites (P < 0.0001) without increased 1,25-dihydroxy vitamin D. Atorvastatin and active metabolite concentrations (P < 0.001) as well as LDL-cholesterol and total-cholesterol levels (97 +/- 28 mg/dl vs. 83 +/- 30 and 169 +/- 35 mg/dl vs. 157 +/- 37, P < 0.005) were lower during vitamin D supplementation. The conclusion of the study is that vitamin D supplementation lowers atorvastatin and active metabolite concentrations yet has synergistic effects on cholesterol concentrations.

A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis.

OBJECTIVE: A lack of published pharmacokinetic data on statins in sepsis has prompted concerns about their safety and toxicity. This study determined single dose pharmacokinetics of Atorvastatin administered orally to acutely ill patients. DESIGN, SETTING AND PARTICIPANTS: A prospective open label study conducted in a tertiary referral centre on 5 healthy volunteers, 5 acutely ill patients admitted to the medical ward and a heterogeneous cohort of 25 critically ill patients admitted to an intensive care unit. INTERVENTION: All participants received a single oral dose of 20 mg of atorvastatin. MEASUREMENT AND RESULTS: Plasma pharmacokinetics of atorvastatin as measured by maximal plasma concentration (Cmax) and area under the curve (AUC) (0-24 h). Critically ill patients with sepsis had a significantly higher Cmax and AUC as compared to healthy volunteers [110.5(86.5) vs. 5.9(2.50) ng/ml, p < 0.01 and 1,051(810) vs. 67(48) ng h/ml (p < 0.0001)], respectively. Atorvastatin concentrations in the plasma of critically ill patients with sepsis remained supratherapeutic for up to 20 h after a single dose. The AUC was significantly higher for those patients on concomitant CYP 450 inhibitor therapy as compared to those patients not on inhibitors (1,518 +/- 793 vs. 584 +/- 540 ng h/ml, p = 0.0260). CONCLUSIONS: Very high plasma concentrations were achieved in intensive care patients with sepsis. This can only be partly explained by altered metabolism of atorvastatin. Further investigations are essential to better describe the pharmacokinetics of statins in various groups of critically ill patients. Caution should be exercised prior to adopting high dose regimens in patients with severe sepsis.

High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial.

BACKGROUND: Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle. METHODS: Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up. RESULTS: The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin. CONCLUSIONS: High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.

Effect of the statin atorvastatin on intracellular signalling by the prostacyclin receptor in vitro and in vivo.

Prostacyclin plays a central role within the vasculature. We have previously established that the prostacyclin receptor (IP) undergoes isoprenylation, a lipid modification obligate for its function. The aim of the current study was to investigate the effect of the hydroxy methyl glutaryl co-enzyme A reductase inhibitor atorvastatin on signalling and function of the IP expressed in mammalian whole cells and in platelets isolated from patients undergoing therapeutic intervention with atorvastatin. Initially, the effect of atorvastatin on signalling by the human (h) and mouse (m) IP overexpressed in human embryonic kidney 293 cells and the hIP endogenously expressed in human erythroleukaemic 92.1.7 cells was investigated. Atorvastatin significantly reduced IP-mediated cAMP generation (IC(50) 6.6-11.1 microm) and [Ca(2+)](i) mobilization (IC(50) 7.2-16.4 microm) in a concentration-dependent manner, but had no effect on signalling by the nonisoprenylated beta(2) adrenergic receptor or the alpha or beta isoforms of the human thromboxane A(2) receptor (TP). Moreover, atorvastatin significantly reduced IP-mediated crossdesensitization of signalling by TP alpha (IC(50) 10.4 microm), but not by TP beta. In contrast to the whole-cell data, atorvastatin therapy did not interfere with IP-mediated cAMP generation or IP-induced inhibition of TP-mediated aggregation of platelets isolated from human volunteers undergoing therapeutic intervention with atorvastatin (10-80 mg per daily dose). In conclusion, while data generated in whole cells indicated that atorvastatin significantly impairs signalling by both the hIP and mP, the in vivo clinical data indicated that, at the administered therapeutic dose, atorvastatin does not significantly compromise IP signalling and function in humans.