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.

1. The metabolism of eugenol (4-hydroxy-3-methoxy-allylbenzene) was investigated in male and female healthy volunteers. It was rapidly absorbed and metabolized after oral administration and was almost completely excreted in the urine within 24 h. Unmetabolized eugenol excreted in urine amounted to less than 0.1% of the dose. 2. The urine contained conjugates of eugenol and of nine metabolites. The structures of these metabolites, elucidated using g.l.c.-mass spectrometry, and by comparison with synthetic reference compounds, were identified as: eugenol, 4-hydroxy-3-methoxyphenyl-propane, cis- and trans-isoeugenol, 3-(4-hydroxy-3-methoxyphenyl)-propylene-1,2-oxide, 3-(4-hydroxy-3-methoxyphenyl)-propane-1,2-diol, and 3-(4-hydroxy-3-methoxyphenyl)-propionic acid. 3. The structures of the following metabolites were tentatively deduced from mass spectra only, as reference compounds were not available: 3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-allylbenzene, 3-(6?-mercapto-4-hydroxy-3-methoxyphenyl)-propane, and 2-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-propionic acid. 4. The amounts of the individual metabolites excreted were determined by g.l.c. Some 95% of the dose was recovered in the urine, most of which (greater than 99%) consisted of phenolic conjugates; 50% of the conjugated metabolites were eugenol-glucuronide and sulphate. Other metabolic routes observed were the epoxide-diol pathway, synthesis of a thiophenol and of a substituted propionic acid, allylic oxidation, and migration of the double bond.

Abstract. Two to 20% of ingested oxalate is absorbed in the gastrointestinal tract of healthy humans with a daily 800 mg calcium intake. Calcium is the most potent modifier of the oxalate absorption. Although this has been found repeatedly, the exact correlation between calcium intake and oxalate absorption has not been assessed to date. Investigated was oxalate absorption in healthy volunteers applying 0.37 mmol of the soluble salt sodium [ 13 C 2 ]oxalate in the calcium intake range from 5 mmol (200 mg) calcium to 45 mmol (1800 mg) calcium. Within the range of 200 to 1200 mg calcium per day, oxalate absorption depended linearly on the calcium intake. With 200 mg calcium per day, the mean absorption (Ϯ SD) was 17% Ϯ 8.3%; with 1200 mg calcium per day, the mean absorption was 2.6% Ϯ 1.5%. Within this range, reduction of the calcium supply by 70 mg increased the oxalate absorption by 1% and vice versa. Calcium addition beyond 1200 mg/d reduced the oxalate absorption only one-tenth as effectively. With 1800 mg calcium per day, the mean absorption was 1.7% Ϯ 0.9%. The findings may explain why a low-calcium diet increases the risk of calcium oxalate stone formation.For decades, a mainstay in the treatment of patients with calcium (Ca) urinary stones has been a Ca-restricted diet (1). Reduction of the Ca content of the diet reliably reduced the amount of Ca excreted in urine. This reduction was believedbut never proven-to reduce the risk of Ca stone formation. By contrast, already in 1969, a Ca-restricted diet was shown to increase the gastrointestinal absorption of oxalate (2), leading to increased amounts of oxalate in the urine and an increased risk of the formation of Ca oxalate stones. Therefore, to reduce oxalate absorption and the resulting risk of formation of Ca oxalate stones, high-Ca supplements were routinely prescribed to obese patients after ileal bypass surgery (3). The reason why these contradictory and confusing recommendations persisted for so long is the lack of prospective studies and the fact that analysis of oxalate remained unreliable (4) until the mid-1980s. Consequently, the amount of dietary oxalate excreted in urine and its role for renal stone formation were underestimated (5). The fact that a low-Ca diet emerged as a risk factor for Ca oxalate calculi and that a high-Ca diet emerged as a protective factor in two large epidemiologic studies (6,7) is still frequently ignored. Hence, the advice to restrict Ca may still be given to patients with recurrent Ca oxalate urinary stones.We wanted to clear up the confusion generated by the contradictory results as well as the contradictory recommendations, and to answer the following question: To what extent does Ca intake influence the gastrointestinal oxalate absorption? Therefore, we quantitatively measured the dependence of oxalate absorption on Ca intake. The physiologic daily dietary Ca intake lies between approximately 370 and 1200 mg. Intakes of less than 300 mg Ca never occur in adults except in those who reduce food intake to lose weight. ...

The evaluation of urinary risk profiles of the patients on their usual dietary habits revealed a high risk for calcium oxalate stone formation. A low fluid intake and an increased intake of protein and alcohol were identified as the most important dietary risk factors. The shift to a nutritionally balanced diet according to the recommendations for calcium oxalate stone formers significantly reduced the stone forming potential.