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Biomedical subjects

R H Levy

Publications and source records attributed to R H Levy.

At least 127 records · Page 7Linked to original sources
PubMed1980

Valproic acid dosage and plasma protein binding and clearance.

Valproic acid clearance was determined in six normal subjects during a single-dose (250-mg) study and multiple-dose experiments of 500, 1,000, and 1,500 mg/day. Eight consecutive oral doses were taken at 12-hr intervals at each dosing level. Valproate levels and protein binding were determined at steady state. Clearance declined 20% from 8.33 +/- 2.44 to 6.67 +/- 1.25 ml/hr/kd between the single-dose and the 500-mg/day steps (p = 0.05). Clearance was unchanged between the 500- and 1,000-mg/day steps despite a 44% increase in mean free fraction (0.0703 +/- 0.0381 vs 0.1011 +/- 0.0438, p < 0.05), implying a balanced opposing decline in intrinsic clearance (from 89.2 +/0 71.0 to 72.0 +/- 20.8 ml/hr/kg; p = 0.025). In four subjects completing the 1,500-mg/day step, clearance increased from 6.76 +/- 1.48 ml/hr/kg (1,000- mg/day) to 8.20 +/- 1.62 ml/hr/kg, corresponding to a further increase in free fraction. Free fraction varied within a single dosing interval (%SD = 11% to 49%). The apparent dose-related decline in intrinsic clearance suggests autoinhibition or saturation of metabolism.

Adult↗
PubMed1980

Kinetics of a carbamazepine-ethosuximide interaction.

Carbamazepine and ethosuximide are used together to treat epileptic mixed-seizure patterns. Since carbamazepine has been shown to induce drug-metabolizing enzyme(s) in the liver, it follows that carbamazepine may alter ethosuximide disposition. Six normal subjects took one 250-mg ethosuximide capsule twice each day for 55 consecutive doses (study days 1 to 28) and one 200-mg carbamazepine tablet each evening from study days 11 to 27. Plasma samples were collected on study days 10, 17, 21, and 28. Mean steady-state concentrations of ethosuximide declined by 17% from a preinduction (study day 10) level of 32.2 +/- 5.6 micrograms/ml to a postinduction level of 26.8 +/- 5.2 micrograms/ml on study day 28. Ethosuximide clearance increased (alpha = 0.05) between study days 10 and 28 from 0.664 +/- 0.120 to 0.800 +/- 0.0154 l/hr. The time course of induction was analyzed using a kinetic induction theory. Ethosuximide half-life was lowered from mean - 53.7 +/- 11.5 hr (before induction) to mean = 44.6 +/- 10.7 hr (after induction); the difference between some subjects was large. These data show that ethosuximide disposition is altered by carbamazepine.

Adult↗
PubMed1980

Phenobarbital--valporic acid interaction.

The effect of subchronic valproate treatment on the single-dose kinetics of phenobarbital was investigated in 6 normal subjects. The study consisted of 2 drug treatments assigned through randomized crossover design. In one treatment subjects received a 60-mg dose of phenobarbital orally. In the other, subjects received 250 mg valproic acid orally twice daily for 14 consecutive days and a 60-mg dose of phenobarbital orally on day 4. Nineteen plasma samples (over 12 days) and two 48-hr urine samples were collected during each treatment. Plasma and urine phenobarbital levels were determined by gas chromatograph interfaced with mass spectrometer in a chemical ionization mode (GLC/CI/MS) and plasma valproic acid levels by GLC. Valproic acid induced several changes in the elimination parameters of phenobarbital: (1) phenobarbital half-life rose from 96 to 142 hr (p = 0.006); (2) plasma clearance fell from 4.2 to 3.0 ml/hr/kg (p = 0.009); (3) renal clearance was unchanged, and metabolic clearance fell from 3.3 to 2.0 mg/hg/kg (p = 0.006); and (4) the fraction of dose excreted unchanged rose from 0.22 to 0.33 (p = 0.015), and the fraction of dose metablized fell from 0.78 to 0.67 (p = 0.015). The findings indicate that valproic acid inhibits phenobarbital metabolism.

Adult↗
PubMed1980

Intramuscular absorption of carbamazepine in rhesus monkeys.

The intramuscular absorption characteristics of carbamazepine were investigated in a group of six chair-adapted rhesus monkeys from three parenteral formulations [A:100 mg/ml of carbamazepine in PEG-400; B:50 mg/ml of carbamazepine in PEG-400; and C:50 mg/ml of carbamazepine in a PEG-400-Tween-80 mixture (9:1)]. The absolute bioavailability was determined by administering formulations A or B intravenously. The kinetic profiles obtained after intramuscular administration suggested biphasic absorption in the majority of animals: an initial rapid absorption phase yielding peak concentrations in less than 1 hr followed by a slower phase where absorption was probably rate limiting. The absolute bioavailability was 38% from formulation A, 81% from formulation B and 82% from formulation C. In two of four cases, Tween-80 eliminated the rate-limiting absorption phase. The data suggest that an intramuscular formulation of carbamazepine with acceptable bioavailability may be feasible.

Animals↗
PubMed1980

Cinromide's metabolite in monkey model: gastric administration and seizure control.

In a previous study (Lockard et al., 1979) Cinromide (3 bromo-N-ethylcinnamamide), an experimental anticonvulsant (Burroughs-Wellcome Pharmaceutical Co.), was given a preliminary evaluation. Since that research was concerned primarily with EEG paroxysms, the present study was conducted to address drug efficacy in terms of clinical seizures. Cinromide's major metabolite (3-bromocinnamamide, BC) was the main focus. Eight alumina-gel monkeys were given by gastric bolus every 6 hr for 10 days (Phase I) either the solvent alone (Tween 80), Cinromide (BEC), or its synthetic metabolite (SBC). Subsequently (Phase II), four animals were given BEC or SBC by chronic gastric infusion for 20 days. In both phases Cinromide's metabolite (either via BEC or especially SBC) was effective in half of the animals in reducing seizure frequency and/or duration at plasma levels above 5 mcg/m. The data suggest that the drug's efficacy is individually specific. Another species of Cinromide metabolism, 3-bromocinnamic acid, is also discussed.

Animals↗
PubMed1980

Meal-dependent absorption of enteric-coated sodium valproate.

The effect of meals on valproic acid (VPA) absorption from an enteric coated (EC) formulation was investigated. In study I, six adult normal volunteers received a single 500 mg dose of sodium valproate in randomized treatments: fasting (A), with a meal (B) or 3 hours after a meal (C). There were significant differences between treatments in the latency period (Lp) defined as the time during which measured concentrations of VPA were less than 1 microgram/ml. Lp values for treatments A, B and C were: 1.67 +/- 1.25 hr, 6.75 +/- 3.98 hr and 7.63 +/- 3.15 hr respectively. In study II, six subjects (five from study I) received in a randomized fashion a 400 mg intravenous bolus dose of VPA and a 500 mg EC VPA tablet, 3 hours after a meal. The mean Lp value was 8.1 +/- 1.6 hr and the mean bioavailability was 100%. Clearance, volume of distribution and half-life values obtained after intravenous dosing were comparable to literature values. These results indicate that food intake delays but does not decrease the extent of absorption of VPA from an enteric coated formulation.

Adult↗
PubMed1980

Phenytoin: biopharmacology.

Among the characteristics of PHT described herein, the following may have some implications in studies of its mechanisms of action: 1. The pKa of PHT may be closer to physiological pH than reported initially. 2. Effective concentrations higher than its solubility at 37 degrees C must involve a binding phenomenon. 3. PHT produces a direct and reversible antieplieptic effect; proposed mechanisms must be compatible with the observed time course of antiepileptic effects. 4. PHT itself is probably solely responsible for its effect. 5. The time course of effect will probably be influenced by dose-dependent kinetics of several species.

Animals↗
PubMed1980

Phenytoin pharmacokinetics in burned rats and plasma protein binding of phenytoin in burned patients.

Unexpectedly low serum phenytoin levels occurred in burned epileptic patients, suggesting the possibility of altered phenytoin disposition. Subsequently, phenytoin log-linear elimination kinetics after a 10 mg/kg i.v. single dose was examined in a burned rat model. Clearance increased from 1.08 +/- 0.28 liters/hr/kg in control rats to 1.50 +/- 0.38 liters/hr/kg in burned rats (P less than .05). The volume of distribution increased from 0.82 +/- 0.058 liters/kg in control rats to 1.01 +/- 0.11 liters/kg in burned rats (P less than .0005). The first order elimination rate constant (KE) did not change significantly (1.31 +/- 0.37) hr-1 in control rats vs. 1.52 +/- 0.48 hr-1 in burned rats; P greater than .05). The increase in clearance and in volume of distribution could be explained on the basis of a decrease in plasma protein binding. The free fraction in plasma increased from 27.1% +/- 1.2 in controls to 33.4% +/- 1.6 in burned rats (P less than .0005). The change in binding was consistent with a decrease in serum albumin from 2.64 +/- 0.33 g/dl in controls to 1.98 +/- 0.16 g/dl in burned rats (P less than .0005). Plasma samples of four burned human subjects revealed low serum albumin and markedly decreased plasma protein binding of phenytoin (2- to 3-fold increase in free fraction in plasma).

Adult↗
PubMed1979

Effects of carbamazepine on valproic acid kinetics in normal subjects.

Carbamazepine and valproic acid are used together in the treatment of epilepsy. It is therefore, relevant to investigate the possibility of a carbamazepine effect on valproic acid disposition, particularly since carbamazepine is known to induce enzymes. We gave valproic acid orally to 6 normal subjects, 250 mg twice daily for 4 wk. Carbamazepine, 200 mg once daily, was begun after 4 days on valproic acid. Serum drug concentrations were measured during 4 dosing intervals, once before and 3 times after beginning carbamazepine. Minimum steady-state concentrations of valproic acid declined after carbamazepine from 34.4 +/- 5.1 to 27.1 +/- 4.4 mug/ml (p less than 0.0005). Clearance rose from 6.46 +/- 0.80 to 8.48 +/- 2.28 ml/hr/kg (p less than 0.01). The increase in clearanace and decrease in minimum steady-state levels was apparent only after 2 wk on carbamazepine. The elimination rate constant (KE) during the dosing interval did not rise during carbamazepine administration (0.0623 +/- 0.0168 hr--1 before and 0.0573 +/- 0.0168 hr--1 after, p greater than 0.25), raising the possibility of an increase in distribution volume.

Adult↗
PubMed1979

Kinetics of biotransformation of clonazepam to its 7-amino metabolite in the monkey.

The pharmacokinetic behavior of the 7-amino metabolite of clonazepam administered exogenously and formed endogenously from the parent drug was studied in a group of rhesus monkeys using constant rate intravenous infusions. Plasma levels of the 7-amino metabolite and/or clonazepam were determined with a GC-CI-MS method. The biological half-life of the 7-amino metabolite (2.2 +/- 1.0 hr) was shorter than that of clonazepam (4.9 +/- 0.2 hr). Total body clearance of the metabolite (0.83 +/- 0.16 liters/hr/kg) was larger than that of the parent drug (0.55 +/- 0.09 liters/hr/kg). The kinetics of in vivo biotransformation were described by a two-compartment model in which formation and disposition of the metabolite follow first-order processes. The fraction of a dose of clonazepam appearing in the systemic circulation as 7-amino metabolite was 0.70 +/- 0.30. This value may underestimate the actual fraction formed, if the metabolite is susceptible to first-pass metabolism following in situ formation.

Amines↗
PubMed1979

Time-dependent kinetics. V: Time course of drug levels during enzyme induction (one-compartment model).

Equations were derived to describe the time course of drug levels during auto- and heteroinduction under a variety of input conditions. These equations were based on a pharmacokinetic theory of induction which assumes that metabolic clearance increases exponentially to a maximum value and that the rate of this increase is governed by the degradation rate constant of the induced enzyme (k'). Closed form solutions could be obtained only for intravenous single-dose (case I) and multiple-dose (case IV) administration. For each of the other cases, constant-rate intravenous infusion (case III), oral single-dose administration (case II), and multiple-dose administration (case V), an exact solution (not closed form) and an approximation (closed form) were derived. Two sets of equations were derived for each of the five cases to take into consideration the possibility of a latency term (lambda). Plots of drug amount X (or concentration C) vs. time (t) were constructed. In case I, a log X vs. t plot was convex, the slope increasing with time. In case II, X increased, reached a peak, and decayed as in case I. In case III (lambda greater than 5 ln 2V/Q) C reached a preinduction steady state before decreasing to a lower (induced) steady state. The behavior of C vs. t for cases IV and V was similar to that for case III. Determination of parameters was attempted in case III. Nonlinear least-square fitting of generated data with 3-9% error yielded reasonable estimates of k'.

Enzyme Induction↗
PubMed1979

Efficacy and toxicity of the solvent polyethylene glycol 400 in monkey model.

Several antiepileptic drugs, such as carbamazepine and clonazepam, have low bioavailability in solid form and are insoluble in an aqueous solution. Alcohol solvents are often employed as vehicles when these drugs are studied in animal models. Secondary and particularly tertiary alcohols are suspected of some anticonvulsant activity. The present research evaluated the possibility that polyethylene glycol 400 (PEG 400) might be efficacious, toxic, or both. Monkeys (N = 11) rendered epileptic by aluminum-hydroxide were administered PEG 400 by constant rate (1 ml/hr) intravenous infusion for 3--4 weeks, preceded and followed by several weeks of baseline. At a concentration of 60%, PEG 400 significantly reduced seizure frequency, but also exhibited severe side effects. These findings suggest that experimental testing of anticonvulsants may be compromised when this or similar solvents are used chronically.

Aluminum Hydroxide↗
PubMed1979

Valproic acid binding to human serum albumin and determination of free fraction in the presence of anticonvulsants and free fatty acids.

The interaction between valproic acid (VPA) and human serum albumin (HSA) was investigated using the equilibrium dialysis technique under various conditions. Solutions of VPA in HSA (2 x 10(-4) M) were dialyzed against isotonic phosphate buffer at 37 degrees C. Protein and buffer compartments were assayed for VPA by GLC. The free fraction (alpha) of VPA increased from 0.13 at 27 microgram/ml to 0.49 at 103 microgram/ml. Scatchard plots were linear, indicating the existence of one type of binding site. The mean (+/- % SD) number of binding sites per macromolecule was 2.06 +/- 3.7% and the mean (+/- % SD) association constant was 2.69 x 10(4) +/- 15.0% liters/mole. The effects of three anticonvulsants (phenytoin, phenobarbital, and carbamazepine) and four major free fatty acids (FFA) (stearic, palmitic, oleic, and linoleic) on alpha were studied. The free fraction, 0.18, was not affected by phenobarbital (20 and 40 microgram/ml), carbamazepine (10 and 20 microgram/ml) or phenytoin (20 and 40 microgram/ml). Each of the four FFA caused a significant increase in alpha: 19--48% increase at 100 microgram/ml of FFA and 88--118% at 200 microgram/ml.

Anticonvulsants↗
PubMed1979

Carbamazepine revisited in a monkey model.

In a previous study on carbamazepine (Lockard et al., 1974), the problem of its low bioavailability in solid form and its short half-life in monkey were addressed. The present research was designed to evaluate carbamazepine under constant-rate intravenous infusion in our alumina-gel monkey model. Since carbamazepine is insoluble in an aqueous solution, polyethylene glycol 400 was used as the vehicle for administration of this drug to a group of 8 epileptic monkeys. The attenuation of seizures by carbamazepine was not statistically significant since the serum levels of carbamazepine after enzyme induction were less than 2.0 micrograms/ml. This study (a) illustrates that some problems in drug evaluation may be insoluble with our present technology even though we are cognizant of them; (b) makes explicit the fact that the efficacy of carbamazepine is a function of adequate serum levels; (c) demonstrates endogenous oscillations of carbamazepine serum concentrations; and (d) reports simultaneous serum levels of carbamazepine and its 10--11 epoxide in the monkey model.

Animals↗