Valproate pharmacokinetics

Malloy MJ, Ravis WR, Pennell AT, Diskin CJ. Effect of cholestyramine resin on single dose valproate pharmacokinetics. Int J Clin Pharmacol Ther 1996 34(5) 208-11. 

Webster LK, Mihaly GW, Jones DB, Smallwood RA, Phillips JA, Vajda FJ. Effect of cimetidine and ranitidine on carbamazepine and sodium valproate pharmacokinetics. Eur J Chn Pharmacol 1984 27(3) 341-3. 

Amitriptyline and nortriptyline plasma levels can be increased by sodium valproate and valpromide, but in contrast, an isolated report attributes a paradoxical rise in serum desipramine levels to the withdrawal of valproic acid. Valproate pharmacokinetics may be moderately affected by amitriptyline. Status epilepticus has been attributed to elevated clomipramine levels in a patient taking valproic acid. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

The pharmacokinetics of distribution and elimination of sodium valproate in mice and dogs has been reported by Schobben and van der Kleijn (12). 

A preliminary pharmacokinetic profile of sodium valproate in monkey has been written by Levig, et. al. (15). 

The short chain fatty acids include butyrate derivatives Hke phenylbu-tyrate, AN-9 (pivaloyloxymethyl butyrate) and valproate. Unfortimately, these compounds have poor potency and pharmacokinetic properties, including short half-life. Numerous Phase I studies with phenylbutyrate, in various oral and intravenous schedules [118-120] have been performed, with neurological toxicity at higher doses being reported. AN-9 showed initial promise in a Phase I study, where the MTD was not reached [121]. The subsequent Phase II study in nonsmall cell lung cancer in 47 patients resulted in fatigue, nausea and dysgeusia as common toxicities. Three partial responses (PR)... 

Nakashima, M., Takeuchi, N., Hamada, M., Matsuyama, K., Ichikawa, M. and Goto, S. (1994) In vivo microdialysis for pharmacokinetic investigations a plasma protein binding study of valproate in rabbits. Biolo ccd el Pharmaceutical Bulletin, 17, 1630-1634. 

Crawford P, Chadwick D, Cleland P, Tjia J, Cowie A, Back DJ, Orme ML. The lack of effect of sodium valproate on the pharmacokinetics of oral contraceptive steroids. Contraception 1986 33(l) 23-9. 

Other uses of valproate include management of bipolar disorder and migraine prophylaxis. Pharmacokinetics... 

Booth CL, Pollack GM, Brouwer KL. Hepatobiliary disposition of valproic acid and valproate glucuronide use of a pharmacokinetic model to examine the rate-limiting steps and potential sites of drug interactions. Hepatology 1996 23(4) 771-780. 

Consider the difference in response to drugs between older and younger people. Treatment should reflect biological age (rather than chronological). Pharmacokinetics, pharmacodynamics, tolerability, adverse reactions, economy and patient choice will all influence therapy chosen. Most commonly, car-bamazepine or sodium valproate are chosen for older people as their effects in older people are well documented. Both show a favourable balance of safety, efficacy and economy. Phenytoin is less preferable because of drug interactions, adverse effects and potential for toxicity (zero order kinetics). 

Yoshioka H, Ida S, Yokota M, Nishimoto A, Shibata S, Sugawara A, Takiguchi Y. Effects of lithium on the pharmacokinetics of valproate in rats. J Pharm Pharmacol 2000 52(3) 297-301. 

No likely pharmacokinetic Interactions of valproate with lithium or atypical antipsychotics... 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

Gidal BE, Anderson GD, Rutecki PR, Shaw R, Lanning A. Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentaUy disabled patients with epilepsy. Epilepsy Res 2000 42(1) 23-31. 

Kanner AM, Frey M. Adding valproate to lamotrigine a study of their pharmacokinetic interaction. Neurology 2000 55(4) 588-91. 

The pharmacokinetic interaction of phenytoin with valproate is complicated (78-80). Initially, the total serum phenytoin concentration falls, because valproate displaces phenytoin from protein binding sites and so the unbound fraction increases, with a consequent increase in clearance. Because of the change in unbound fraction the total plasma concentration effect curve is shifted to the left, and a lower total concentration is as effective as the total phenytoin concentration was in the absence of valproate. However, valproate also inhibits the metabolism of phenytoin and so the serum phenytoin concentration then starts to rise and there is a risk of toxicity. 

Loscher, W. (1978) Serum protein binding and pharmacokinetics of valproate in man, dog, rat and mouse. Journal of Pharmacology and Experimental Therapeutics, 204, 255-261. 

In comparison with phenytoin and carbamazepine, which induce changes in TGS of several hundred microampere, the effects of the fatty acids were rather small. However, a more conspicuous difference was the slow increase in threshold over a period of several hours. With intravenous administration of phenytoin, carbamazepine, or valproate, the maximal effect is reached almost immediately after injection, after which the threshold returns to baseline in 4—6 h. The pharmacokinetics were not investigated in detail, but the time-course of effect certainly did not follow the plasma concentration. Blood samples taken from some rats that were treated with DHA or EPA indicated that the plasma concentration was maximal at the end of the infusion and dropped to undetectable levels after 6 h (probably already after 3 h). 

I Pharmacokinetics. Valproate sodium is rapidly converted to valproic acid in the stomach, whereas divalproex sodium delayed-release and extended-release tablets must pass into the small intestine to be converted to valproic acid. Valproic acid is highly bound to albumin and other plasma proteins, and it is extensively metabolized in the liver. A summary of the absorption, distribution, metabolism, and elimination data for valproate is found in Table 68-11. ... 

Anticonvulsants Carbamazepine decreases the plasma concentration of bupropion to about 90% even after a single dose of 150 mg of carbamazepine. Long-term administration of valproate (a weak inhibitor of hepatic metabolism) has no effect on bupropion plasma concentration. It has been shown that bupropion does not cause clinically relevant changes in the pharmacokinetics of a single dose of 100 mg of lamotrigine. 

Thus, valproate is often used to reduce the risk for clozapine-induced seizures. Carbamazepine can potentially increase the risk for development of agranulocytosis when coadministered with clozapine, so this combination should be avoided. Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its half-life by about 20%. To date, no pharmacokinetic interactions have been reported between aripiprazole and valproate. 

DeVane CL. Pharmacokinetics, drug interactions, and tolerability of valproate. Psychopharmacol Bull 2003 (Summer) 37 25-42. 

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