St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro‐drug) and pravastatin were determined in this study.
Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double‐blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24‐hour period after the administration of each drug.
Repeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P < .05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration‐time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P < .05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half‐life of simvastatin or pravastatin between the placebo and St John's Wort trials.
This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4‐mediated first‐pass metabolism of simvastatin in the small intestine and liver.
Clinical Pharmacology & Therapeutics (2001) 70, 518–524; doi:
Abstract. HMG-CoA reductase inhibitors (statins) have been shown to decrease cardiovascular mortality. Since ventricular tachyarrhythmias are closely related to cardiovascular mortality, we tested effects of the hydrophilic statin pravastatin and the lipophilic statin fluvastatin in a rat arrhythmia model of ischemia / reperfusion and simultaneously measured serum total cholesterol level. Anesthetized rats were subjected to 5-min ischemia and 10-min reperfusion after chronic administration of oral pravastatin (0.02, 0.2, or 2 mg / kg), fluvastatin (0.2, 2, or 4 mg / kg), or vehicle for 22 days, once daily. The acute effect of pravastatin (0.2 or 2 mg / kg, once orally) was also observed. Chronically administrated pravastatin significantly reduced the incidence of ischemia-induced ventricular tachycardia (VT) from 70% (control) to 9% at 2 mg / kg, and it reduced the incidence of reperfusion-induced lethal ventricular fibrillation (VF) from 90% (control) to 20% at 0.2 mg / kg. Acute pravastatin and chronically administrated fluvastatin had no significant effect on these arrhythmias. There were no significant changes in blood pressure, heart rate, QT interval, and serum cholesterol among pravastatin-, fluvastatin-, and vehicletreated groups. Hydrophilic pravastatin prevented reperfusion-induced lethal VF in anesthetized rats by chronic administration independent of its cholesterol lowering effect. This may be a new beneficial role of pravastatin in decreasing cardiovascular mortality.
We encountered two cases of pediatric living-related liver transplant recipients who showed increases in blood concentration of cyclosporine or tacrolimus, a dual substrate for cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), during a diarrheal episode. To investigate the effect of intestinal inflammation on the metabolic and efflux pump activities, we conducted the experiments using the lipopolysaccharide (LPS)-induced intestinal damage model. Intestinal epithelial CYP3A activity was assessed by nifedipine oxidation using intestinal epithelial microsomes in rat. Drug efflux by P-gp was tested using digoxin flux with the excised intestine perfusion system in rats. Intraperitoneal injection of LPS (0.3 mg/kg) significantly reduced the intestinal epithelial CYP3A activity by 41% (p < 0.01). In the proximal jejunal segment of the rats treated with LPS, mucosal to serosal flux of digoxin was significantly enhanced compared to that of control (p < 0.05). Efflux of digoxin, which was taken up by intestinal epithelium, to mucosal perfusate was significantly blunted in the jejunum treated with LPS (p < 0.05), which indicates that the LPS treatment reduced the P-gp activity in rat small intestine. These findings suggest that the suppression of CYP3A and P-gp activities may be involved in the mechanism of elevated blood concentrations of cyclosporine and tacrolimus during enteritis-induced diarrhea. To prevent a drug-induced adverse effect, dose of a drug, which is a substrate of CYP3A or P-gp, should be reduced during such an episode.
Cardiac surgery with cardiopulmonary bypass (CPB) induces a whole body inflammatory response that sometimes leads to postoperative organ dysfunction, and neutrophil activation plays an important role in this reaction. Neutrophil priming has been described as a change in neutrophil status such that neutrophils show enhanced responsiveness to a second activating stimulus. We hypothesized that neutrophil priming occurs by cardiac surgery with CPB and is temporally related to the neutrophilia after surgery. To evaluate primed circulatory neutrophil status, we measured aggregation activity stimulated by N-formyl-methyl-leucyl-phenyl-alanine (FMLP) and free radical producing activity by tumor necrosing factor (TNF) alpha in peripheral blood samples. Eleven adult patients undergoing elective cardiac surgery with CPB were studied. Blood samples were taken before surgery, at the end of bypass, 12 h after surgery, and 7 days after surgery. Aggregation activity and superoxide generation were significantly elevated 12 h after surgery when compared to presurgery values, indicating that cardiac surgery is associated with circulatory neutrophil priming. The number of neutrophils markedly increased at the end of cardiopulmonary bypass and reached a peak 12 h after surgery. The circulatory neutrophils of cardiac surgical patients become primed after surgery, coincident with the peak neutrophil count. These results suggest that circulatory neutrophils after cardiac surgery with CPB have enhanced responsiveness and are predisposed to systemic inflammation.
AimSt John's Wort (SJW) enhances CYP3A4 activity and decreases blood concentrations of CYP3A4 substrates. In this study, the effects of SJW on a benzodiazepine hypnotic, quazepam, which is metabolized by CYP3A4, were examined.
MethodsThirteen healthy subjects took a single dose of quazepam 15 mg after treatment with SJW (900 mg day -1 ) or placebo for 14 days. The study was performed in a randomized, placebo-controlled, cross-over design with an interval of 4 weeks between the two treatments. Blood samples were obtained during a 48 h period and urine was collected for 24 h after each dose of quazepam. Pharmacodynamic effects were determined using visual analogue scales (VAS) and the digit symbol substitution test (DSST) on days 13 and 14.Results SJW decreased the plasma quazepam concentration. The C max and AUC 0-48 of quazepam after SJW were significantly lower than those after placebo [ C max ; -8.7 ng ml -1 (95% confidence interval (CI) -17.1 to -0.2), AUC 0-48 ; -55 ng h ml -1 (95% CI -96 to -15)]. The urinary ratio of 6 b -hydroxycortisol to cortisol, which reflects CYP3A4 activity, also increased after dosing with SJW (ratio; 2.1 (95%CI 0.85-3.4)). Quazepam, but not SJW, produced sedative-like effects in the VAS test (drowsiness; P < 0.01, mental slowness; P < 0.01, calmness; P < 0.05, discontentment; P < 0.01). On the other hand, SJW, but not quazepam impaired psychomotor performance in the DSST test. SJW did not influence the pharmacodynamic profile of quazepam.
ConclusionsThese results suggest that SJW decreases plasma quazepam concentrations, probably by enhancing CYP3A4 activity, but does not influence the pharmacodynamic effects of the drug.
These results suggest that O2- production by circulatory PMNs is augmented in SHR, but not in L-NAME and DOCA/salt hypertensive rats. This enhanced function, which is also observed in human essential hypertension, might contribute to the development of cardiovascular damage in genetically determined hypertension.
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