The pharmacokinetics of quercetin, a flavonoid, have been studied in 6 volunteers after single intravenous (100 mg) and oral (4 g) doses. The data after iv administration were analyzed according to a two compartment open model with half lives of 8.8 +/- 1.2 min for the alpha phase and 2.4 +/- 0.2 h for the beta phase (predominant half life), respectively. Protein binding was greater than 98%. The apparent volume of distribution was small at 0.34 +/- 0.03 1/kg. Of the intravenous dose 7.4 +/- 1.2% was excreted in urine as a conjugated metabolite, and 0.65 +/- 0.1% was excreted unchanged. After oral administration no measurable plasma concentrations could be detected, nor was any quercetin found in urine, either unchanged or in a metabolized form. These results exclude absorption of more than 1% of unchanged drug. Recovery in faeces after the oral dose was 53 +/- 5%, which suggests extensive degradation by microorganisms in the gut. The data obtained show that oral administration of flavonoids may be of questionable value.

Valproic acid is rapidly absorbed from the gastrointestinal tract, peak concentrations being attained I to 2 hours after administration of the conventional tablet, but later with the entericcoated tablets. The bioavailability of valproic acid is complete and independent of the preparation used. The apparent volume of distribution is relatively small CO. I to 0.4 L/ kg), due to high plasma protein binding. Protein binding is decreased in patients with renal insufficiency, in patients with chronic liver disease, and possibly in the presence of other displacing agents.The total plasma clearance of valproic acid is in the range of 5 to 10ml/min. Plasma elimination half-life is between /0 and 16 hours, and does not change after continued treatment with valproic acid alone. In combination therapy with other antiepileptic drugs, the halflife can be as short as 6 to 8 hours due to liver enzyme induction. Renal excretion of unchanged va/proic acid accounts for only 1 to 3 % of the total dose. Va/proic acid is present in . cerebrospinal fluid in concentrations equal to the unbound drug in plasma' (around 10 % of the total concentration). Valproic acid concentration in saliva is less than and unrelated to thi/ree drug concentration in plasma. The drug is excreted into breast milk and evidence suggests that it also crosses the placenta. Four independent metabolic pathways -glucuronidation, ~-oxidation and w"oxidation (WI and Wl) have been demonstrated in man. Analytica/ difficulties caused by the similarity of the metabolites with many normal endogenous compounds and by chemical lability of several metabolites impede the isolation, identification and especially the quantification of valproic acid metabolites. Quantitative aspects of metabolism are essentialIor the understanding of drug effects in patients. The main metabolite 3-oxo-valproic acid shows comparable pharmacological activity to valproic acid itself in mice; unsaturated metabolites .also show some activity.In young infants under 2 months of age valproic acid elimination half-life can be 60 hours, but in older children, plasma elimination appears to be identical to the adult situation: Valproic acid elimination is impaired in acute viral hepatitis imd in liver cirrhosis: No information is available. on valproic acid kinetics in renal insufficiency.Phenobarbitone plasma concentrations rise· under combinaiion therapy with valproic acid, because phenobarbit~ne elimination is impaired. Va/proic acid lowers total plasma co~centra-Supported by Sandoz Foundation for Therapeutic Research.

Cimetidine is the first histamine H2-receptor antagonist with wide clinical application. It is a weak base and a highly water-soluble compound which can be measured in biological fluids by a number of high-pressure liquid chromatographic methods. Following intravenous administration, the plasma concentration profile follows multicompartmental characteristics. The total systemic clearance is high (500 to 600 ml/min) and is mainly determined by renal clearance. The volume of distribution (Vd beta or Vdss) is of the order of 1 L/kg and this about equals bodyweight. Elimination half-life is approximately 2 hours. Following oral administration of cimetidine, 2 plasma concentration peaks are frequently observed, probably due to discontinuous absorption in the intestine. The absolute bioavailability in healthy subjects is about 60%. In patients with peptic ulcer disease, bioavailability is around 70%, but the variation is much greater than in healthy subjects. Absorption and clearance of cimetidine are linear after 200 and 800mg doses. Mean steady-state plasma concentrations on a standard 1000mg daily dose are 1.0 microgram/ml (range 0.64-1.64 micrograms/ml) and are reproducible after treatment periods of up to 2 years. When taken with food, the extent of absorption is unaltered, but a delay occurs and only 1 peak in the plasma concentration curve is apparent. Partial gastrectomy (Billroth I, II) causes an increase in systemic availability of cimetidine by an unclear mechanism. Distribution of cimetidine leads to extensive uptake into kidney, lung and muscle tissues. It distributes into the cerebrospinal fluid (CSF) at a ratio of 0.1 to 0.2 compared with plasma. The mean saliva to plasma ratio is 0.2 (range 0.1-0.55). Plasma protein binding is 20%, and there is no relevant effect of changes in binding on the pharmacokinetics of cimetidine. Uptake of cimetidine into red blood cells leads to concentrations equal to those in plasma. Between 50 and 80% of the dose administered intravenously is recovered in urine as unchanged cimetidine. This fraction is less after oral doses, but is independent of the amount of the dose. In ulcer patients, 40% is recovered unchanged in urine after oral administration. Biliary excretion of cimetidine accounts for only 2% of the dose.(ABSTRACT TRUNCATED AT 400 WORDS)

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