Objective 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. Methods 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. Results 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. Conclusions 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:
AimsThere have been case reports of taste disturbance for the angiotensin II receptor blockers losartan and valsartan, but not for candesartan. This study was undertaken to examine whether candesartan causes taste disturbance. Methods Candesartan cilexetil (4 mg day-1 ) or vehicle was given to healthy volunteers ( n = 8) for 7 days in a randomized, double-blind, placebo-controlled, cross-over design with a 2-week washout period. Clinical gustometry using the filter-paper disc test and electrogustometry were sequentially performed before and at the end of each trial. Serum and salivary zinc concentrations were also measured. ResultsDetection thresholds of four basic tastes (sweet, salty, sour and bitter) determined by the paper disc test were significantly ( P < 0.05 in all tests) worsened (i.e. score of test increased) after repeated dosing of the drug, although the subjects did not notice such changes. The mean ± SEM (and 95% CI) scores of the four tastes at just before the seventh dosing of candesartan or vehicle was 3.38 ± 0.32 (3.02, 3.74) and 2.63 ± 0.18 (2.18, 3.08) for sweetness, 3.63 ± 0.38 (4.49, 2.77) and 2.63 ± 0.26 (3.27, 1.98) for salt, 4.01 ± 0.42 (3.04, 4.98) and 2.61 ± 0.32 (3.35, 1.87) for sourness, 4.01 ± 0.38 (3.22, 4.80) and 2.99 ± 0.33 (2.24, 3.74) for bitterness, for candesartan and placebo, respectively. Electrogustometry confirmed the candesartan-related taste disturbance. Serum and salivary zinc concentrations were not influenced by candesartan. ConclusionsThese data suggest that candesartan subclinically reduces taste sensitivity after repeated dosing in healthy subjects. Because similar events are repor ted for losartan and valsartan in case reports, this adverse effect might be a class effect of angiotensin-II receptor blockers (ARBs).
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