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Biomedical subjects

R H Levy

Publications and source records attributed to R H Levy.

At least 109 records · Page 6Linked to original sources
PubMed1982

Kinetics of phenobarbital in normal subjects and epileptic patients.

The kinetics of phenobarbital (PB) were evaluated in six normal subjects and six epileptic patients treated with phenytoin or carbamazepine. Each normal subject received three single doses of PB: PB-sodium 130 mg i.v. (IV), PB sodium 10 mg i.m. (IM), and PB acid 100 mg orally (PO), in random order at least one month apart. After IV PB distributive half-lives were 75 to 126 h, steady state volume of distribution (Vss) was 0.54 +/- 0.03 l/kg, and clearance (CL) was 3.8 +/- 0.77 ml/h/kg. Absolute bioavailability of IM PB was 101 +/- 11%. Peak serum PB concentrations were achieved from 2 to 8 h after IM administration, and from 0.5 to 4 h after PO administration. Epileptic patients exhibited similar PB kinetics: disposition half-lives were 77 to 128 h, Vss 0.61 +/- 0.05 l/kg, and Cl 3.9 +/- 0.76 ml/h/kg. Phenobarbital appears to represent an exception among antiepileptic drugs, in that pharmacokinetic data obtained in normal car reasonably be extrapolated to the epileptic population.

Administration, Oral↗
PubMed1982

Induction effect of phenobarbital on carbamazepine-10,11-epoxide kinetics in the rhesus monkey.

A previous study showed that coadministration of phenobarbital (PB) and carbamazepine (CBZ) to the rhesus monkey resulted in an increase in the steady-state ratio of carbamazepine-10,11-epoxide (EPO) to CBZ. Several postulates were proposed suggesting in induction in the formation pathway of EPO. This study was undertaken to determine whether PB can also modify the elimination kinetics of EPO in monkey. Five rhesus monkeys received an intravenous bolus dose of EPO on day 1, day 5, and day 15. In addition, the animals received an acute loading dose (110 mg) of PB on day 5 followed by 10 daily maintenance doses (35 mg/day). Plasma samples were assayed for PB and EPO by GC/CI/MS. The mean (+/- SD) of plasma clearance (CL), volume of distribution (V), and half-life (t 1/2) during the control period for EPO were 5.57 +/- 2.15 liters/hr, 7.48 +/- 2.50 liters and 0.95 +/- 0.16 hr, respectively. An acute loading dose of PB had no significant effect on any of these pharmacokinetic parameters at p = 0.05. Subchronic administration of PB caused an increase in CL (8.23 +/- 2.03 liters/hr, p less than 0.05), a decrease in t 1/2 (0.67 +/- 0.09, p larger than 0.05 but less than 0.10), and no change in V. This study suggests that PB produces an increase in systemic and intrinsic hepatic clearance of EPO. Therefore, the reported increase in the EPO-CBZ steady-state ratio after PB administration could occur only if the formation clearance of EPO is increased to a greater extent than its elimination clearance.

Animals↗
PubMed1982

Ethosuximide kinetics: possible interaction with valproic acid.

Ethosuximide kinetics were determined in six normal healthy adults after a single dose (phase 1) and at steady-state (phase 2). After the completion of phase 2, valproic acid was added to the ethosuximide regimen (phase 3) to assess the possibility of drug interaction. Between phases 1 and 2 total clearance fell from 13.1 to 11.1 ml/hr/kg (P less than 0.05) and nonrenal clearance fell from 10.1 to 8.3 ml/hr/kg (P less than 0.05). When valproic acid was added (phase 3) there was no further change in total or nonrenal clearance (11.2 and 8.3 ml/hr/kg). To assess the possibility of nonlinear ethosuximide kinetics a review was conducted of patients who received ethosuximide as sole therapy for absence seizures. Of 106 patients, 10 met the required criterion that defined steady state. Data from seven of the 10 patients showed evidence of a nonlinear relationship when steady-state ethosuximide concentrations were plotted against dose.

Adult↗
PubMed1982

Systemic interaction between valproic acid and free fatty acids in rhesus monkeys.

The interaction between valproic acid (VPA) and free fatty acids (FFA) was investigated at a systemic level in eight rhesus monkeys. Intralipid emulsion (I.L.) was infused to increase plasma FFA levels. During I.L. treatment, plasma FFA levels were elevated in all cases (12 cases) with increases ranging from 38 to 525% (median, 102%). Valproate free fraction (fp) was elevated in 11 of 12 cases, with increases ranging between 7 and 100% (median, 18%). A positive correlation between the relative increase in FFA and the corresponding increase in fp of VPA was obtained. Intralipid infusion was associated with changes in the systemic clearance of VPA (an increase in five cases and a decrease in seven cases). The intrinsic clearance (Clint) of VPA was decreased in 9 of 12 cases with decreases ranging from 13 to 78% (median, 22%). Urinary excretion of valproate glucuronide was decreased in three of four monkeys during I.L. treatment. A significant positive correlation (p less than 0.05) between the relative increase in FFA levels and the decrease in Clint of VPA were also observed. The mechanism of interaction between VPA and FFA in rhesus monkey is more complex than a simple protein binding displacement and involves at least one metabolic inhibition component such as glucuronidation.

Animals↗
PubMed1982

Diurnal oscillations in plasma protein binding of valproic acid.

In view of the observed variation of valproic acid (VPA) free fraction (fp) during a dosing interval and the competitive binding effect of free fatty acids (FFA) in vitro, this study was designed to address the existence of diurnal variations in the fp of VPA. Six subjects were hospitalized at 7 a.m. for 25 h, and plasma samples were collected every 2 h. The protocol was repeated in 4 of the 6 subjects one week later. In vitro binding of VPA (100 micrograms/ml) was determined by equilibrium dialysis (14C-VPA), and FFAs were assayed colorimetrically. Phenytoin (PHT) binding was also determined for comparison. VPA fp ranged from 8.10 +/- 1.16 to 9.63 +/- 1.54. Intrasubject variability was also measured by the ratio of maximum to minimum fp values (fp max/fp min) over 24 h: This ratio ranged from 1.30 to 1.68 (mean +/- %SD = 1.51 +/- 7.7%, n = 10). For PHT, fp ranged from 10.88 +/- 0.50 to 12.39 +/- 1.07, and fp max/fp min from 1.09 to 1.31 (1.17 +/- 5.1%, n = 10). The fp max was observed between 2 and 6 a.m. in 7 out of 10 cases for VPA and 5 out of 10 cases for PHT. FFA levels, although in the normal range, varied two- to fourfold within 24 h. A significant correlation was observed between mean FFA levels at each sampling time and the corresponding fp values for VPA (p less than 0.001), but not for PHT.

Adolescent↗
PubMed1982

Serum quinidine determination: comparison of mass-spectrometric and extraction-fluorescence methods.

A comparison of two analytical methods of quinidine plasma determination--the modified extraction fluorometric method and the mass spectrometric method--was made. Plasma supplies collected at steady state from normal human volunteers participating in a bioavailability study were analyzed, using both methods. A total of 359 samples were analyzed. Comparison of both sets of values, by linear regression, yielded an r2 value of 0.84. The results of this comparison were consistent with the results reported by others, confirming that the commonly used extraction fluorometric method of quinidine determination is sufficiently accurate for monitoring quinidine plasma concentrations in the patient care setting, as well as for bioavailability comparisons between products.

Humans↗
PubMed1982

Drug interactions with valproic acid.

Valproic acid undergoes drug-drug interactions with most of the commonly used anticonvulsants. Since it possesses a wide range of indications, concomitant use with other anticonvulsants, and hence interactions, are not infrequent. Many of these interactions are reciprocal and may have important therapeutic consequences. Valproate acts as a protein binding displacer and/or metabolic inhibitor with respect to a number of other anticonvulsants (phenobarbitone, primidone, phenytoin). Inhibition of metabolism would, in most instances, result in a decrease of the dose requirements of the affected drugs. Valproate is a low clearance drug primarily eliminated by metabolism. Its metabolism is highly inducible by some of the major anticonvulsants (e.g. carbamazepine, phenytoin). Valproate is also highly protein bound in plasma and thus is displaced by salicylates and free fatty acids. However, displacement alone, unlike induced metabolism, should not affect the drug's dose-response relationship.

Anticonvulsants↗
PubMed1981

Plasma protein binding interaction between valproic and salicylic acids in rhesus monkeys.

The effects of three levels of salicylic acid on the steady-state plasma concentrations of free and total valproic acid were examined in catheterized rhesus monkeys. Valproate was infused intravenously for a total of 41 hr, and salicylate was added after the first 8 hr. The three salicylate infusions were randomly assigned to each monkey. Valproate free fraction was determined by equilibrium dialysis. Statistically significant increases in valproate free fraction and total body clearance were observed after addition of salicylic acid. The increase in valproate clearance was positively correlated with the molar ratio of salicylate to valproate steady-state plasma concentrations. There was no significant change in valproate free concentration after salicylate treatment. The proposed mechanism of this in vivo interaction includes plasma protein binding displacement with no change in valproate intrinsic clearance.

Animals↗
PubMed1981

Differential kinetics of cinromide and two of its metabolites in epileptic patients.

Cinromide is an experimental anticonvulsant currently in phase II testing. A single oral dose (900 mg) of cinromide was administered to 8 epileptic subjects on phenytoin therapy. Plasma samples drawn during the next 36 h were analyzed for cinromide and its amide and acid metabolites. The absorption rate of cinromide varied widely between subjects producing maximum cinromide concentrations between 0.5 and 2.5 h after the dose. The median elimination half lives of cinromide and the amide and acid metabolites were 0.73, 1.65, and 4.85 h respectively. The oral clearance of cinromide (median = 135 l/h) suggests that it is subject to first pass metabolism. In all subjects the area under the curve (AUC) of acid metabolite (632 to 1777 microM/l) was greater than the AUC of amide metabolite (77 to 185 microM/l) which was greater than the AUC of cinromide (5 to 89 microM/l). Steady-state concentration ratios of metabolite to parent drug predicted from the AUC data were 3.8 for the amide and 35.8 for the acid metabolite. The amide metabolite is known to have anticonvulsant properties and, until the relative contributions of metabolites and parent drug to the efficacy of cinromide are resolved, the monitoring of metabolites as well as parent drug is imperative.

Adult↗
PubMed1981

Metabolite to parent drug concentration ratio as a function of parent drug extraction ratio: cases of nonportal route of administration.

The ratio of metabolite to parent drug concentration (Cm/Cp) of a medium or high extraction ratio (E greater than 0.1) drug administered intravenously has been shown to depend on intrinsic clearance of drug by other metabolic routes (CLr,int) as well as on organ blood flow (Q). In contrast, for a low extraction ratio drug given intravenously or for any drug given by a portal route, this ratio is equal to the ratio of formation clearance (CLf,int) and metabolite clearance (CLm,int). The sensitivity of Cm/Cp to changes in CLr,int and CLf,int has been analyzed quantitatively. It was shown to be dependent on the fraction metabolized to that particular metabolite (fm).

Animals↗
PubMed1981

Clonazepam acetylation in fast and slow acetylators.

Six slow acetylators (SAs) and six rapid acetylators (RAs), as determined by sulfamethazine (SMZ) phenotyping, were each given a 2-mg oral dose of clonazepam. Ninety-six-hour urine collections from these subjects were analyzed for clonazepam, 7-amino clonazepam (7-AM, clonazepam nitroreduced metabolite), and 7-acetamido clonazepam (7-ACT, N-acetylated 7-AM). The SA group excreted more 7-AM and less 7-ACT than the RA group; mean (+/- Sd) recovered as 7-AM was 22.7 +/- 5.0% for the SA group and 13.6 +/- 4.1% for the RA group and mean (+/- SD) recovered as 7-ACT was 1.5 +/- 0.4% for the SA group and 3.9 +/- 1.8% for the RA group. Both differences were substantial (p less than 0.02 by unpaired t test) and indicate that the rate of acetylation of 7-AM to 7-ACT in the biotransformation of clonazepam is determined by the acetylator phenotype.

Acetylation↗
PubMed1981

Protein binding of valproic acid in the presence of elevated free fatty acids in patient and normal human serum.

Two recent reports indicate that free fatty acids (FFA) can decrease the binding of valproic acid (VPA) to plasma proteins. Since FFA can increase in several physiological and clinical situations, it becomes necessary to define the relationship between elevated FFA and VPA free fraction. This study was conducted in two phases. In the first phase, serum was obtained from nine patients who were receiving Intralipid. A base-line sample was taken when therapy was absent. A second sample was taken during or immediately after Intralipid therapy. Protein binding VPA (equilibrium dialysis) and FFA levels were determined on each sample. FFA increased in eight patients; the median increase was 80.1%. VPA free fractions increased in six of the eight patients showing an increase in FFA; the median increase in free fraction was 18.7%. Rank correlation between FFA differences and free fraction differences indicated a significant positive linear correlation (r = 0.800). In the second phase, oleic acid was added to normal serum in five different concentrations (500-5,000 microEq/liter) with VPA at 100 microgram/ml. Free fraction of VPA increased continuously from a blank value of 9.6% (+/- 1.4) to 44.1% (+/- 2.5) with increasing concentrations of oleic acid.

Fat Emulsions, Intravenous↗
PubMed1981

Phenytoin--valproic acid interaction in rhesus monkey.

The interaction between phenytoin (PHT) and valproic acid (VPA) was investigated in the rhesus monkey. PHT was given by multiple IV bolus to reach a steady state and then continued while two successive VPA infusions were added. Plasma was assayed for total VPA and PHT as well as free PHT. The addition of VPA produced no change in total PHT levels, a 50% increase in PHT free fraction (increase in free PHT levels), and a decrease in PHT overall elimination rate constant. The increase in free fraction was also documented in a separate in vitro study. The increase in free PHT levels suggested that VPA decreased PHT intrinsic metabolic clearance. This interaction may thus involve a dual mechanism-namely protein binding displacement of PHT and inhibition of PHT metabolism. This mechanism is compatible with other studies showing that VPA is an inhibitor of drug metabolism.

Animals↗
PubMed1981

Induction effect of phenobarbital on the carbamazepine to carbamazepine-10, 11-epoxide pathway in rhesus monkeys.

The induction effect of phenobarbital on the carbamazepine to carbamazepine-10, 11-epoxide pathway was investigated in seven rhesus monkeys. Each animal received an 8-hr infusion of carbamazepine on days 1, 5 and 15. In addition, animals received an acute dose (130 mg) of phenobarbital on day 5 followed by 10 daily maintenance doses (40 mg). Plasma samples were assayed for phenobarbital, carbamazepine and epoxide by gas chromatography interfaced with a mass spectrometer in chemical ionization mode. The control mean +/- S.D. values of plasma clearance, volume of distribution and T1/2 for carbamazepine were 7.3 +/- 2.37 liters/hr, 9.61 +/- 2.29 liters and 0.96 +/- 0.02 hr, respectively. The control steady-state ratio of epoxide to carbamazepine was 0.065 +/- 0.023. An acute loading dose of phenobarbital caused an apparent decrease in clearance (6.05 +/- 1.80 liters/hr, P = .06) with no apparent changes in other parameters. Subchronic administration of phenobarbital resulted in increases in clearance (14.42 +/- 4.91 liters/hr, P = .006) and volume distribution (12.00 +/- 2.06 liters, P = .01), a decrease in T1/2 (0.62 +/- 0.15 hr, P = .006) and an apparent increase in the epoxide to carbamazepine steady-state ratio (0.085 +/- 0.013, P = .06). The increase in the epoxide to carbamazepine ratio after subchronic administration of phenobarbital suggests that phenobarbital induces the formation of epoxide more than its elimination. This is in direct contrast to the lowering of the epoxide to carbamazepine ratio by carbamazepine autoinduction.

Animals↗
PubMed1980

Simultaneous analysis of phenobarbital and p-hydroxyphenobarbital in biological fluids by GLC-chemical-ionization mass spectrometry.

A sensitive and specific GLC-chemical-ionization mass spectrometric method was developed for the simultaneous assay of phenobarbital (I) and p-hydroxyphenobarbital (II) in biological fluids (urine and plasma) using stable isotope analogs of the compounds as internal standards. After extraction, the compounds were methylated with diazomethane and quantitated by GLC-chemical-ionization mass spectrometry. The detection limit of the method was 0.1 micrograms/ml for both compounds. The intraday precision (RSD) for 0.4-2.4 micrograms/ml was < 2% for I and < 4% for II. The interday precision for 0.55 and 2.11 micrograms/ml of each compound was 5.5 and 2.9% for I and 7.3 and 5.0% for II, respectively. This method has been applied in several pharmacokinetic studies.

Gas Chromatography-Mass Spectrometry↗