Lowered plasma concentrations humans

Cyclosporin A is slowly but extensively metabolized. The biotransformation pathway and the pattern of the generated metabolites are similar in humans and animals. Approximately 17 single metabolites have been detected so far, all of which are present in considerably lower plasma concentration than cyclosporin A itself [46]. Eleven ether-extractable compounds have been isolated from urine of dog and man and from rat bile and faeces using preparative HPLC and thin-layer chromatography [43]. Structural assignments for these... 

The normal plasma concentration in the rat is 0.9 mmol/L and in the human is 0.6 mmol/L. It is likely to be lower in other body fluids, e.g. lymph, interstitial fluid. 

Human clinical studies Plasma levels of hyperforin were followed for 24 hours in two studies with healthy volunteers after administration of film-coated tablets containing 300 mg SJW extract representing 14.8 mg hyperforin (Table 2) (72). In the first crossover study, six male volunteers received 300, 600, or 1200 mg of a SJW extract preparation (WS 5572, Dr. Willmar Schwabe Arzneimittel, Karlsruhe, Germany) after a 10-hour fasting time. Maximum plasma levels of 150 ng/mL (approximately 280 nM) were reached after 3.5 hours after intake of 300 mg SJW extract. Half-life and MRT were 9 and 12 hours, respectively. Hyperforin pharmacokinetics were linear up to 600 mg of the extract. Increasing the doses to 900 or 1200 mg resulted in lower Cmax and AUC values than those expected from linear extrapolation of data from lower doses. In a repeated dose study with seven healthy volunteers, no accumulation of hyperforin in plasma was observed after intake of 900mg/day SJW extract for seven days. The estimated steady-state plasma concentrations of hyperforin after intake of 3 x 300mg/day was approximately 100 ng/mL (approximately 180 nM) (Table 2) (72). 

In human subjects, however, 8 weeks of vitamin E supplementation (800 IU/day) to the diet produced a lowered plasma PGI2 level, as measured by 6-keto-PGF1(X, compared with that in non-supplemented controls [129]. Addition of vitamin E to human platelets in concentrations which resemble normal plasma levels produced a moderately potent but consistent reduction in cyclo-oxygenase activity, with a dose-dependent response up to 1 mM. a-Tocopherol quinone was equally effective in this test [ 130]. 

Saponins appear to lower plasma LDL cholesterol concentration by interfering with cholesterol absorption. Studies in rats and monkeys fed naturally occurring saponins exhibited significant reductions in cholesterol absorption efficiency and an increase in fecal cholesterol excretion (Malinow et al., 1981 Nakamura et al., 1999 Sidhu et al., 1987). Decreased bile acid absorption and increased excretion has also been reported in animals fed saponins (Malinow et al., 1981 Nakamura et al., 1999 Stark and Madar, 1993). One possible mechanism of action for decreased cholesterol absorption is the ability of saponins to form insoluble complexes with cholesterol (Gestetner et al., 1972 Malinow et al., 1977). In an effort to isolate the specific properties of saponins, Malinow (1985) prepared a variety of synthetic saponins in which the complex carbohydrate moieties of native plant saponins were replaced with simplified carbohydrates such as glucose or cellobiose. One of these synthetic saponins, tiqueside (Pfizer, Inc.), can effectively precipitate cholesterol from micelle solutions in vitro and inhibit cholesterol absorption in a variety of animals (Harwood et al., 1993) and in humans (Harris et al., 1997). But despite ample data showing the formation of a saponin/cholesterol complex in vitro, there is essentially no definitive evidence that complexation occurs in the intestinal lumen (Morehouse et al., 1999). 

A liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed [33] and validated for the determination of donepezil in human plasma samples. Diphenhydramine was used as the IS. The collision-induced transition m/z 380 > 91 was used to analyze donepezil in selected reaction monitoring mode. The signal intensity of the m/z 380 —> 91 transition was found to relate linearly with donepezil concentrations in plasma from 0.1 to 20.0 ng/ml. The lower limit of quantification of the LC/MS/MS method was 0.1 ng/ml. The intra- and inter-day precisions were below 10.2% and the accuracy was between 2.3% and +2.8%. The validated LC/MS/MS method was applied to a pharmacokinetic study in which healthy Chinese volunteers each received a single oral dose of 5 mg donepezil hydrochloride. The non-compartmental pharmacokinetic model was used to fit the donepezil plasma concentration-time curve. Maximum plasma concentration was... 

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