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Biomedical subjects

R H Levy

Publications and source records attributed to R H Levy.

At least 91 records · Page 5Linked to original sources
PubMed1984

Disposition of progabide and valproic acid following intraperitoneal administration in rhesus monkey.

The pharmacokinetic characteristics of progabide, a new gamma-aminobutyric acid-mimetic drug, were evaluated following single- and multiple-dose administration of a progabide suspension through a chronic intraperitoneal catheter. Several issues pertaining to the bioavailability of progabide were addressed: first-pass effect, incomplete dissolution, and dose and time dependency. Four male monkeys received five treatments: three intraperitoneal doses (50, 100, and 150 mg), one oral dose (50 mg), and one intravenous bolus dose (150 mg). Bioavailability following intraperitoneal administration was incomplete, consistent with a first-pass effect predicted from intravenous data. There were no significant differences between the absolute bioavailabilities of the three intraperitoneal doses, which ranged between 40 and 49%. The apparent half-life (t 1/2) observed after intraperitoneal administration was significantly longer than the elimination half-life by the intravenous route and tended to increase with dose. This behavior is consistent with dissolution rate-limited absorption. The bioavailability of the suspension administered orally was compared with that of the intraperitoneal route, and no difference was found. However, the apparent t 1/2 by the oral route was significantly longer than that of the intraperitoneal route. In multiple-dosing studies, four different dosing regimens (all intraperitoneal) were examined, including 50 mg every 2 or every 6 h, 20 mg every 2 h, and 40 mg every 4 h. In all these regimens, plasma levels exhibited an accumulation compared with single-dose predictions. Large oscillations in plasma levels were observed when the dosing interval was 6 h and side effects were observed when the dosing interval was 2 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1984

Carbamazepine/valproic acid interaction in man and rhesus monkey.

Sodium valproate (VPA) was administered for 1 week (1 g b.i.d.) to seven epileptic patients receiving chronic carbamazepine (CBZ) therapy. Steady-state CBZ levels determined before and after VPA therapy were reduced by 3-59% in six patients and were unchanged in one patient. The plasma concentration ratio of carbamazepine-10,11-epoxide ( CBZE ) to CBZ increased in all patients by 11-500%. The plasma binding of CBZ was determined in six healthy volunteers given a single 400 mg CBZ dose with and without the coadministration of 1 g VPA in a cross-over design. The mean CBZ free-fraction was increased in three of the subjects (p = 0.008-0.031), decreased in one subject (p less than 0.002), and remained unchanged in two subjects when VPA was administered. Four male rhesus monkeys were infused intravenously with CBZ (15 mg h-1) for 5 days and then three consecutive 24-h infusions were given: I, CBZ alone; II, CBZ with 75 mg h-1 VPA; III, CBZ with 150 mg h-1 VPA. The mean free-fraction of CBZ and CBZE increased during infusions II and III from 31.5 +/- 2.7% to 33.6 +/- 2.6% (p less than 0.05) and 37.7 +/- 1.3% (p less than 0.01) for CBZ and from 46.9 +/- 9.2% to 53.6 +/- 5.7% (p greater than 0.05) and 60.1 +/- 4.0% (p less than 0.01) for CBZE . The clearance of free CBZ declined from 7.96 +/- 1.75 to 4.84 +/- 1.26 (p less than 0.01) and 4.12 +/- 1.75 (p less than 0.01) 1 kg-1h-1 during infusions II and III, respectively. The mean free CBZE /CBZ ratio increased from 0.12 +/- 0.03 to 0.24 +/- 0.03 and 0.36 +/- 0.04 during infusions II and III, respectively (p less than 0.001). These findings indicate a decrease in the elimination clearance of CBZE possibly coupled with a decrease in its formation clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1984

Rationale for monitoring free drug levels.

Recent developments in our knowledge of drug binding prompt the questions, in what circumstances are measurements of free levels necessary, desirable or not warranted? Free level monitoring should be considered for drugs for which the usefulness of plasma level monitoring has been established, drugs which are highly bound to plasma proteins, and which exhibit a variable free fraction. In terms of drug distribution, free drug concentration is independent of free fraction, while total concentration is a resultant of free concentration and free fraction. For drugs with a low extraction ratio, the total concentration at steady-state depends upon free fraction, but the free concentration is independent of free fraction. With high extraction ratio drugs, the free concentration is dependent upon free fraction but only after parenteral administration. There are numerous examples of drugs which are highly bound and exhibit large variations in free fraction. Free fraction may increase with drug concentration. Pathophysiological changes in the binding ligands, albumin and alpha 1-acid glycoprotein, as well as changes in the concentration of endogenous compounds which compete for binding sites, may also cause changes in free drug fraction. Binding interactions resulting from polytherapy may also result in a variable free fraction. Ultrafiltration devices now enable the convenient and accurate determination of free drug levels. Areas in which this should prove useful are investigations of concentration-effect relationships and clinical situations requiring intensive monitoring where binding changes are suspected.

Aged↗
PubMed1983

Pharmacokinetic relationships between cinromide and its metabolites in the rhesus monkey I: 3-Bromocinnamamide, an active metabolite.

Fifty percent of a cinromide dose was metabolized to an active metabolite in the rhesus monkey. The steady-state concentration of this metabolite was 3-6 times that of the parent drug, depending on the route of administration. Cinromide is a medium-extraction ratio drug with a short half-life (0.92 +/- 0.23 hr) when compared with the active metabolite, which has a low extraction ratio and a longer half-life (4.43 +/- 0.76 hr). Incomplete oral bioavailability of cinromide is a result of first-pass metabolism rather than incomplete absorption.

Animals↗
PubMed1983

Steady-state determination of the contribution of lung metabolism to the total body clearance of drugs: application to carbamazepine.

A steady-state approach is proposed to examine the contribution that the lung makes to the total body elimination of medium- to high-clearance drugs. Carbamazepine, a potential candidate of pulmonary metabolism, was investigated by infusion into the femoral vein in seven unrestrained Sprague-Dawley rats (250-300 g). Blood samples (0.45 ml), taken simultaneously from the jugular vein and carotid artery in each rat during the infusion (2-5 days), were assayed in duplicate for carbamazepine by GLC/CI/MS. Venous blood concentrations were used to calculate the total body clearance of carbamazepine, 440 +/- 38 ml/hr (mean +/- SEM), and the difference between simultaneous venous and arterial blood concentrations were used to calculate the extraction ratio of carbamazepine by the lung. The mean extraction ratio of 0.0058 (n = 28) suggests that the lung only contributes approximately 5% to the total body clearance of carbamazepine. It is proposed that this technique could be useful in examining the importance of the lung in the total body clearance of other drugs, and that it has several advantages over some currently used techniques.

Animals↗
PubMed1983

Time-dependent kinetics VII: effect of diurnal oscillations on the time course of carbamazepine autoinduction in the rhesus monkey.

Extensive blood sampling and repeated long-term carbamazepine infusions were carried out in four rhesus monkeys to examine the time course of carbamazepine autoinduction in detail and assess the intraanimal variability in the rate constant of induction. Diurnal oscillations in carbamazepine blood levels were observed during all infusions and these prevented a good data fit for the biochemical model previously proposed for describing the decline in drug blood levels during induction by carbamazepine. An attempt at fitting only selected blood samples to the model resulted in variable (and perhaps questionable) induction rate constants, even in the same animal. Previous variability in calculated induction rate constants may be due to the presence of diurnal oscillations superimposed on the autoinduction phenomenon. It is proposed that the simultaneous expression of diurnal oscillations and autoinduction are the result of effects on drug metabolism at two independent levels.

Animals↗
PubMed1983

In vivo evaluation of the Michaelis-Menten constant for a medium extraction ratio drug: application to cinromide in the rhesus monkey.

The dose-dependent nonlinearity of the clearance of cinromide, a medium extraction ratio drug, has been established in two monkeys. Special problems encountered in evaluation of nonlinearity of such drugs were resolved by the experimental design: cinromide was infused to steady state via the portal vein. A linearized form of the Michaelis-Menten equation was used to determine Vmax and Km. In addition, cinromide was administered to one of the monkeys via a femoral vein to verify the overestimation of Km by administration at a peripheral venous site.

Animals↗
PubMed1983

No effect of food intake on clobazam absorption.

The kinetics of clobazam taken 3 h before, during, and 3 h after a standard hospital meal were studied in six healthy volunteers. Peak plasma levels were significantly lower when the drug was taken with or after meals suggesting that the rate of absorption was reduced by food. The mean area under the concentration vs time curve was not affected by the time of drug administration indicating that the meal had no effect upon the extent of absorption.

Adult↗
PubMed1983

Pharmacokinetic profile of a new anticonvulsant, stiripentol, in the rhesus monkey.

Stiripentol is a new anticonvulsant drug derived from phenyl-l-pentene-ol. One of its metabolites resulting from opening of the methylenedioxy ring also possesses anticonvulsant activity. This study undertook to define the overall pharmacokinetic profile of stiripentol in rhesus monkey prior to its efficacy evaluation. The experimental design included six treatments (three intravenous doses of 40, 80, and 120 mg; one oral dose of 80 mg; and two intraperitoneal doses of 80 and 120 mg) administered to five chaired rhesus monkeys in a randomized fashion. Sixteen plasma samples were obtained over 7 h and urine was collected for 24 h. A high-performance liquid chromatography assay was developed for the determination of stiripentol in plasma and urine (C8 reverse phase column and UV detection, lambda = 254 nm). The intravenous data revealed multiexponential behavior and therefore noncompartmental methods were used to describe the pharmacokinetics of stiripentol. Values for plasma clearances (L/h/kg) were 1.10 +/- 0.07 (40 mg), 0.92 +/- 0.08 (80 mg), and 0.86 +/- 0.15 (120 mg). The decrease in clearance with dose provided evidence of nonlinearity. The average mean residence time was 1.09 +/- 0.03 h. The average volume of distribution at steady state was 1.03 +/- 0.3 L/kg. The bioavailabilities obtained for the oral and intraperitoneal doses were consistent with first-pass effect predictions: 0.3 (oral), 0.32 (i.p. 80 mg), and 0.34 (i.p. 120 mg). The free fraction determined by equilibrium dialysis was less than 1%. The fraction of dose excreted unchanged in urine ranged between 0 and 3%. The metabolite with anticonvulsant activity could not be detected in plasma with any of the modes of administration. However, it was found in urine and accounted for 2% of the dose. The fraction metabolized by glucuronidation was 34.8 +/- 9.1%. The percentages of total amount of glucuronide excreted in the intervals 0-2, 2-4, 4-8, and 8-24 h were 70.6 +/- 6.2, 10.1 +/- 5.4, 13.6 +/- 5.1, and 5.7 +/- 3.1%. These findings suggested that the terminal phase was not associated with elimination but rather with drug distribution.

Animals↗
PubMed1983

Cinromide in epilepsy: a pilot study.

Monotherapy with the experimental antiepileptic drug cinromide was evaluated in 11 adult outpatients with uncontrolled partial epilepsy. They were treated with phenytoin for 2 months, cinromide for 4 months, and carbamazepine for 4 months. Four patients withdrew from the study during or shortly after crossover to cinromide due to increased seizure frequency or severity. Of the remainder, three preferred carbamazepine, two cinromide, and two phenytoin, based on both seizure control and degree of toxicity. Overall seizure control was not significantly different with any of the three agents, but during cinromide administration secondarily generalized seizure control was uniformly worst and there was also a tendency toward decreased performance on neuropsychological tests. CNS toxicity and gastrointestinal toxicity were prominent during the first month of cinromide treatment, but subsided with time or dose reduction. No abnormalities requiring drug withdrawal were found with laboratory testing. The results suggested, at best, a very limited clinical usefulness for cinromide, and it has been withdrawn from testing by its manufacturer.

Adult↗
PubMed1982

[Is it preferable to prescribe 1 or 2 daily doses of sodium valproate?].

Enteric-coated tablets containing 1 500 mg of sodium valproate (VPA) were administered in a randomized fashion either once or three times a day for 7 days to 6 healthy adult volunteers. Plasma total VPA levels and unbound fractions of the drug were determined 2-hourly on the last day of each treatment. Peak plasma concentrations were higher, and minimum plasma concentrations lower with one single dose than with three doses. In subjects who received three doses, the concentration curves tended to plateau, with higher AUC values. However, none of the differences observed reached statistical significance. The clinical implications of these pharmacokinetic data are discussed.

Adult↗
PubMed1982

Pharmacokinetic profile of progabide, a new gamma-aminobutyric acid-mimetic drug, in rhesus monkey.

The pharmacokinetic profile of progabide was investigated in five chronically catheterized male rhesus monkeys. The experimental design included single-dose intravenous bolus and oral administration at two dose levels (50 and 100 mg) and zero-order intravenous infusion for 7 days. Plasma samples were analyzed by electron-capture-GLC. Protein binding of the drug was determined by equilibrium dialysis (4 degrees). A one-compartment open model with monoexponential decay was proposed to describe the pharmacokinetics. The mean parameters (+/-SEM) of the 50- and 100-mg iv bolus were: total body clearance, 2.09 (+/-0.15) and 1.53 (+/-0.18) liter/hr/kg; half-life, 0.656 (+/-0.054) and 0.789 (+/-0.079) hr; distribution volume, 1.97 (+/-0.08) and 1.79 (+/-0.21) liter/kg. Progabide was highly bound to plasma proteins and also to erythrocytes. The drug was rapidly absorbed (Tmax less than 1 hr at both doses). The mean bioavailability was attributed principally to a first-pass effect. In the constant rate infusion study, systemic clearance was larger than that of the single dose studies.

Administration, Oral↗
PubMed1982

The influence of free fatty acids on valproic acid plasma protein binding during fasting in normal humans.

The effect of physiologic variations of free fatty acid levels on in vivo valproic acid plasma protein binding was studied in 6 healthy adult subjects. 14 blood samples were taken during a 12-h dosing interval at steady state while in a fed condition and also during a 27 h fast. Free fraction and total valproate concentration were determined by equilibrium dialysis and GLC, respectively. Free fatty acid levels were determined from both fresh samples and samples incubated at 37 degrees C for 12 h, the latter in order to simulate equilibrium dialysis conditions. Fasting resulted in increased serum free fatty acid levels in all subjects, ranging from 34-182% (p less than 0.01). Incubation also caused free fatty acid levels to rise, more so in fed samples (50-87%, p less than 0.01) than in fasting samples (10-50%, p less than 0.01). Fasting resulted in a 9% increase in the mean free fraction for all subjects combined (P less than 0.01). Regression analysis of 180 sets of values for free fraction, total valproate concentration and free fatty acid level suggested that valproate concentration accounts for 17% and free fatty acid level for 37% of the variation in free fraction. Mean clearance was unchanged by fasting despite an increased free fraction suggesting decreased intrinsic clearance (i.e. decreased metabolism) of valproate under these conditions.

Adult↗