The pharmacokinetics of the antiepileptic drug, sodium valproate (VPA), was investigated in 6 healthy volunteers after a single intravenous dose of 400 mg, as well as a solution and enteric-coated tablets. The bioavailability of the enteric-coated tablets was compared with that of normal tablets in 3 of these subjects. The bioavailability studies demonstrated that the solution was rapidly and almost completely (86% to 100%) absorbed. Peak plasma levels (66 to 196 f.Lg Iml) were reached within 0.5 to 2 hr. Tablets had comparable bioavailabilities which varied in the different persons (68% to 100%). In some subjects VPA was found in plasma only after a lag time of 1 to 4 hr and the peak plasma concentrations of 46 to 88 f.Lg Iml developed after 3 to 7 hr. After the intravenous dose, plasma levels declined biexponentially. The pharmacokinetic parameters were computed according to the two-compartment open model. The half-life of the initial phase, tlh( a), could be calculated to 1.0 ± 0.86 hr (mean ± SD) and the terminal half-life, tVz( {3), varied independently of the route of administration between 8.7 and 21.5 hr (12.2 ± 3.7 hr). The distribution space of the central compartment (VI) was 0.065 ± 0.010 Llkg, and both the apparent volume of distribution at steady-state (Vd ss ) and Vdf3 had similar values of 0.13 ± 0.04 Llkg and 0.14 ± 0.05 Llkg, respectively. These small volumes indicate that VPA distributes mainly into the extracellular space. The total plasma or blood clearance (Cl) ranged from 4.3 to 10.5 ml!min (7.8 ± 2.4 ml!min) and from 11.9 to 44.3 ml!min (30.1 ± 11.9), respectively. Therapeutic concentrations of VPA (80 f.Lglml) revealed relatively strong plasma protein binding between 80% and 94%. The bloodlplasma concentration ratio ranged about 0.28 ± 0.06. Since the calculated hepatic extraction ratio of 0.02 is smaller than the free fraction, it is concluded that clearance of VPA is independent of liver blood flow and of the restrictive type. No measurable amounts of unchanged VPA were excreted during the 2 days of observation. Approximately 10% to 30% of a single dose was eliminated as VPA conjugates which could be hydrolyzed by 2 N HCI and {3-glucuronidaselaryl-sulfatase.The anti epileptic properties of the branched chain fatty acid sodium valproate (di-n-propylacetate, VPA) were serendipitously discovered by Meunier and associates ll in 1963 when it was used as an organic solvent. In clini-

The effect of the monoamine oxidase inhibitor selegiline on tyramine metabolism and intravenous and oral tyramine pressor sensitivity was studied in healthy subjects. After oral doses of tyramine, which caused systolic blood pressure to increase by 30 mm Hg, we determined plasma concentrations of p-hydroxyphenylacetic acid (HPAA) and of conjugated and unconjugated tyramine. When 20 mg/day of selegiline was administered, the AUCspec of HPAA decreased from 86% to 64% and the AUCspec of conjugated tyramine increased from 13% to 35% of the sum of total tyramine and HPAA. Pressor sensitivity was enhanced more with oral administration of tyramine than with intravenous administration of tyramine. After the drug was discontinued, initial values were reached within 4 days (one subject) and 2 weeks (two subjects). Fifty-five percent of the selegiline dose was eliminated in urine as amphetamine and methamphetamine. The findings support the assumption that selegiline does not selectively inhibit monoamine oxidase-B (MAO-B) when administered in doses of 20 mg/day and higher.

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In seven healthy male volunteers the effects of the pattern of dosing on the pharmacokinetics of diazepam have been studied. A cross-over design was employed that consisted of three parts: a single intravenous dose (0.1 mg/kg), and oral dosing (10 mg/day) for six days followed by an intravenous bolus (0.1 mg/kg) on the seventh day, followed by re-examination of a single intravenous dose after diazepam (D) and its major metabolite desmethyldiazepam (DD) had been completely eliminated. Plasma levels of D and DD were monitored by a specific, sensitive GLC-method. In younger patients (n = 5, age 29 - 35 years) the elimination half-life, T1/2(beta), of D was 33.9 +/- 10.6 h (mean +/- S.D.) after the single dose. The control study gave an almost identical result (35.7 +/- 12.1). After subchronic dosage in all patients T1/2(beta) showed a modest but significant prolongation (paired t-test p less than 0.01) to 52.9 +/- 17.4 h. It was caused by a significant decrease (p = 0.016) in total plasma clearance (Cl), from 26.0 +/- 10.8 ml/min. Older patients (age 43-60 years) showed the same phenomenon. Blood/plasma ratios remained constant indicating no change in protein binding. Biliary excretion of D was measured in five patients with a T-tube. Only negligible amounts (0.3 - 0.4%) of administered D were excreted within 3 days after subchronic dosage, which demonstrates a lack of enterohepatic cycling of D. After multiple administration of D, there was accumulation of DD to levels approximately five times higher than after a single dose. The possibility that the slower elimination of D after subchronic treatment might be caused by DD was also supported by experiments in dogs and rabbits. After pretreating rabbits with DD and maintaining a high DD plasma level, there was prolongation of T1/2(beta) from 2.7 h to 5.2 h, with a corresponding decrease of Cl from 101.6 ml/min to 23.4 ml/min. Similar results were obtained in dogs. It is concluded that the disposition of D is altered by subchronic use and may be regulated by the plasma DD concentration.

The pharmacokinetics of cimetidine area under curve (AUC0-48 h), maximum concentration (Cmax), time to reach Cmax(tmax) and apparent terminal plasma half-life (t1/2) was not changed by co-administration of valsartan. For valsartan, the AUC0-48 h increased by 7% and the Cmax by 51% (ratio of geometric means) with co-administration of cimetidine. The higher value for Cmax was attributed to the initial increase in the rate of absorption of valsartan: ka was increased 2.7-fold and another indicator for the rate of absorption, Cmax/tmax, 2.2-fold. This effect was ascribed to inhibition of acid secretion by cimetidine, which leads to a higher gastric pH, thereby increasing the solubility of valsartan; the t1/2 of valsartan was not changed. After valsartan alone, 19% of the dose was absorbed, 23% with co-administration of cimetidine. It was estimated that only 2.2% of the possible change in AUC might be missed by giving a single high dose of cimetidine instead of multiple doses, with the aim to optimally inhibit formation of the inactive metabolite of valsartan. Cimetidine-related changes in the rate of elimination of valsartan were not anticipated, since the clearance from plasma occurs mainly by biliary excretion of unchanged valsartan; metabolism and renal excretion are only minor contributors. Therefore, even in the clinically relevant situation with multiple doses of valsartan and cimetidine, notable changes in the pharmacokinetics of valsartan, except for an increase in Cmax, are not to be expected. This increase in Cmax appears to be of no clinical significance. Valsartan alone and in combination with cimetidine was well tolerated by healthy subjects.

The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fold). After withdrawal of phenelzine, pressor sensitivity to oral tyramine returned to control values within 2 and for more than 8 weeks. Relative bioavailability of conjugated tyramine was elevated sixfold by brofaromine and 11.6-fold by phenelzine. Urinary elimination of tryptamine increased during phenelzine and brofaromine to 12.7-fold and threefold, respectively. 3-Methoxy-4-hydroxyphenylglycol (MHPG) and 3-methoxy-4-hydroxymandelic acid (VMA) excretion decreased during brofaromine significantly by 72% and 49%, respectively. The nonsignificant decrease of MHPG excretion and the increase of intravenous tyramine pressor sensitivity caused by phenelzine are significantly related. The data suggest that the selective reversible MAO-A inhibitor brofaromine has a larger therapeutic safety than phenelzine.

In six patients with cirrhosis and five patients with fibrosis of the liver elimination of diazepam (D) was compared after single and subchronic dosage. The pharmacokinetics of the major metabolite desmethyldiazepam (DD) was investigated in four healthy individuals and four patients with hepatic dysfunction and compared to its parent compound D. In the initial study, 11 patients with liver disease (cirrhosis and fibrosis) had a longer half-life (T 1/2(beta) of 99.2 +/- 23.2 hr after a single intravenous bolus of 0.1 mg/kg of D than to age-matched normal subjects (46.6 +/- 14.2). After subchronic treatment with 10 mg of D for 7 days T 1/2(beta) was prolonged only slightly (p = 0.043) in these patients (107.6 +/- 25.2 hr). Neither total plasma clearance (Cl) nor the apparent volume of distribution (VdSS or VdCl) showed significant changes. After intravenous injection of DD (0.1 mg/kg) plasma levels declined in the same biexponential manner as after D. The cross-over study in the four normal subjects demonstrated that DD was eliminated much more slowly than D. Whereas for D, T 1/2(beta) and Cl were 32.6 +/- 11.3 hr and 32.3 +/- 11.0 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min. The accumulation of DD after multiple dosage could be explained by the fact that it is formed faster from D than it is eliminated. In four patients with liver disease the elimination of D and the elimination of DD were altered. In these patients T 1/2(beta) for DD was prolonged (p = 0.015) to 108.2 +/- 40.3 hr. This prolongation was caused by a decrease in Cl of 4.6 +/- 1.1 ml/min, (p = 0.003) whereas Vd(Cl) did not change significantly. This indicates that at least two steps in diazepam metabolism are impaired in patients with liver disease.

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