The flavonoid quercetin is metabolized into isorhamnetin, tamarixetin, and kaempferol, the vascular effects of which are unknown. In the present study, the effects of quercetin and its metabolites were analyzed on isometric tension in isolated rat thoracic and abdominal aorta, in isolated intact and ␤-escinpermeabilized iliac arteries, and on perfusion pressure in the isolated mesenteric resistance vascular bed. In noradrenalineprecontracted vessels, the four flavonoids produced a vasodilator effect, which was inversely correlated with the diameter of the vessel studied; i.e., quercetin, isorhamnetin, tamarixetin, and kaempferol were 5-, 25-, 4-, and 6-fold, respectively, more potent in the resistance mesenteric bed (Ϫlog IC 50 ϭ 5.35 Ϯ 0.15, 5.89 Ϯ 0.11, 5.34 Ϯ 0.10, and 5.66 Ϯ 0.06, respectively) than in the thoracic aorta (Ϫlog IC 50 ϭ 4.68 Ϯ 0.08, 4.61 Ϯ 0.08, 4.73 Ϯ 0.11, and 4.81 Ϯ 0.13, respectively; n ϭ 4 -6). The vasodilator responses of quercetin and isorhamnetin were not significantly modified after removal of the endothelium in the thoracic aorta or in the mesenteric bed. Furthermore, the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10 Ϫ6 M), the adenylate cyclase inhibitor SQ22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine; 10Ϫ6 M], KCl (40 mM), or ouabain (10 Ϫ3 M) had no effect on isorhamnetin-induced vasodilation in the mesenteric bed. In permeabilized iliac arteries stimulated with Ca 2ϩ (pCa of 5.9), isorhamnetin was also significantly more potent (Ϫlog IC 50 ϭ 5.27 Ϯ 0.15) than quercetin (Ϫlog IC 50 ϭ 4.56 Ϯ 0.15). In conclusion, quercetin and its metabolites showed vasodilator effects with selectivity toward the resistance vessels. These effects are not due to or modulated by endothelial factors and are unrelated to changes in cytosolic Ca 2ϩ .Flavonoids comprise a large group of secondary metabolites widely distributed throughout the plant kingdom, including food plants. The daily flavonoid intake in the human diet (mainly from onions, apples, grapes, wine, tea, berries, herbs, and spices) is highly variable, with estimations ranging from 23 mg (flavonols plus flavones; Hertog et al., 1993b) to more than 500 mg (total flavonoids;

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The flavonoid quercetin reduces blood pressure and endothelial dysfunction in animal models of hypertension. However, the results concerning the relationship between quercetin and NO present a complex picture. We have analyzed the mechanisms involved in the NO scavenging effects of quercetin and its repercussion on NO bioactivity in vascular smooth muscle. Quercetin scavenged NO with apparent zero-order kinetics with respect to NO. This effect was strongly dependent on the O 2 concentrations, so that NO decay at pH 7.4 could be fitted to the equation

Valproic acid, a branched short-chain fatty acid, has numerous action mechanisms which turn it into a broad spectrum anticonvulsant drug and make its use possible in some other pathologies such as bipolar disorder. It is extensively metabolized in liver, representing β-oxidation in the mitochondria one of its main metabolic route (40%). Carnitine is responsible for its entry into the mitochondria as any other fatty acid. Long-term high-dose VPA therapy or acute VPA overdose induces carnitine depletion, resulting in high levels of ammonia in blood. As a high correlation between salivary valproic acid levels and plasma ultrafiltrate levels was found in humans, saliva becomes a promising monitoring fluid in order to study valproic acid pharmacokinetics and its toxic effect. Extended-release (twice daily) formulations of valproic acid or carnitine supplementation are the proposed two therapeutic strategies in order to reverse hyperammonemia.

Isorhamnetin and quercetin produced endothelium-independent vasodilator effects in rat aorta, rat mesenteric arteries, rat portal vein and porcine coronary arteries. The effects of the two flavonoids were similar in arteries stimulated by noradrenaline, KCl, U46619 or phorbol esters but the two flavonoids were more potent in the coronary arteries than in the aorta. At high concentrations, they also induced a positive inotropic effect in isolated rat atria. Therefore, at least part of the in vivo effects of quercetin may result from its conversion to isorhamnetin which is the main metabolite of quercetin found in plasma. The arterial, venous and coronary vasodilator effects may contribute to the protective effects of flavonoids in ischaemic heart disease observed in epidemiological studies.

Plasma concentration-time data obtained after an oral single dose of 500-mg valproic acid (VPA) in a delayed release formulation was used to model enterohepatic cycling of the drug. Fourteen healthy subjects (seven women and seven men) were enrolled, food intake was standardized, blood samples were withdrawn up to 48 h post dosing and VPA plasma concentrations were analyzed by HPLC-UV method. Secondary peaks of VPA were observed in almost all subjects. A population pharmacokinetic analysis with sex, weight, age and contraceptive therapy as possible covariates was performed. Women without contraceptive therapy presented a longer lag time, a lower VPA hepatic output and a higher reabsorbed fraction than men. Weight affected both volume of the central compartment and the absorption rate constant. Women under contraceptive therapy showed similar disposition parameters to men. Reabsorbed fraction of bioavailable dose was 46.2 % in women and 21.8 % in men, revealing important sex differences in drug hepatobiliar output. These results showed that VPA displays sex-related pharmacokinetic differences due to different metabolic and transporter-mediated disposition.

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