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Biomedical subjects

I H Patel

Publications and source records attributed to I H Patel.

12 recordsLinked to original sources
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↗
PubMed1977

Time-dependent kinetics II: Diurnal oscillations in steady-state plasma ethosuximide levels in rhesus monkeys.

Morning steady-state (9 am) plasma levels were significantly higher than the corresponding evening (5 pm) plasma levels during a 3-week zero-order infusion of ethosuximide to six monkeys. These differences could not be explained by experimental variables such as GLC assay and infusion pump. Circadian periodicity in steady-state plasma levels was investigated in three monkeys over 4 months under controlled experimental conditions: blood sampling at 2-hr intervals for 26 hr, 1 day/week; fixed lighting, feeding, and noise schedules; and electroencephalogram monitoring. The plasma concentration-time curves showed two minima in the 12 noon-2 pm and 8 pm-12 midnight periods, and the later involved the largest percent change in plasma levels (4-8%). The plasma concentration-time data were subjected to cross-correlation analysis, which indicated a circadian rhythm in steady-state plasma levels with a period of 24-26 hr.

Animals↗
PubMed1977

Time-dependent kinetics III: diurnal oscillations in steady-state plasma valproic acid levels in rhesus monkeys.

Valproic acid was administered by constant rate intravenous infusion to catheterized chained rhesus monkeys for 8-10 weeks under controlled environmental conditions. Steady-state plasma levels were monitored at 2-hr intervals for 26 hr (10 am-12 noon on the following day), 1 day/week for 6 weeks. Individual steady-state plasma concentration-time plots exhibited the following characteristics. During Period A (10 am-6 pm), plasma levels remained stable or decreased. During Period B (6 pm-6 am), plasma levels increased, reached a maximum, and remained markedly higher than during Period A. The maximum concentrations were 40-140% higher than the observed minimum concentrations. During Period C (6 am-noon), plasma levels tended to decline from the maximum concentrations achieved in Period B. In most cases, plasma concentrations at 10 am and 12 noon of the 2nd experimental day fell within 10% of their respective values on the previous day. The mean (+/- SD) periods obtained by cross-correlation analysis of individual plasma concentration-time plots were 30.7 (+/- 3.7) and 22.8 (+/- 3.6) hr for Animals 903 and 923, respectively. The corresponding mean (+/- SD) amplitudes were 27.3 (+/- 12.6) and 17.4 (+/- 2.3)%. A circadian rhythm in total body clearance was hypothesized, and its pharmacokinetic implications are discussed.

Animals↗
PubMed1977

Diurnal variation of valproic acid plasma levels and day-night reversal in monkey.

Four normal monkeys each equipped with an EEG plug and two indwelling catheters for drug infusion and sampling, respectively, were administered valproic acid (VPA) before and after a 12-hr light, 12-hr dark phase shift. Before day-night reversal, diurnal oscillations of VPA plasma levels under steady-state intravenous constant-rate infusions were 30-50%, with maximum concentrations during the dark phase of the cycle. After reversal, maximum VPA plasma concentrations tended to follow the dark phase shift. The correlation was not perfect, nor was the sleep cycle completely reversed since the animals slept less after the phase shift. Possible mechanisms of the diurnal plasma level fluctuations and the importance of oscillations of this magnitude to clinical drug regimens are discussed.

Animals↗
PubMed1977

Distribution characteristics of ethosuximide in discrete areas of rat brain.

The distribution properties of ethosuximide in four regions of the rat brain--cortex, midbrain, cerebellum, and pons-medulla--were investigated following chronic intraperitoneal administration of the drug (every 12 hr for 108 hr) at four dose levels (20, 40, 60, and 80 mg/kg). A gas-liquid chromatographic procedure was developed to quantitate ethosuximide levels in these tissues and plasma. The mean tissue/plasma ratios were 0.917, 0.942, 0.902, and 0.903 for cortex, midbrain, cerebellum, and pons-medulla, respectively. The distribution ratio for midbrain was significantly greater than that observed for cerebellum. For each brain region, the distribution ratio was independent of dose (20 to 80 mg/kg) and plasma concentration (8 to 135 microgram/ml).

Animals↗
PubMed1975

Pharmacokinetic properties of ethosuximide in monkeys. I. Single-dose intravenous and oral administration.

The pharmacokinetic profile of ethosuximide was studied in 6 chronically catheterized male rhesus monkeys at three dose levels (30, 60, and 90 mg/kg), intravenously and orally. Plasma and urine levels were assayed by GLC. The intravenous and oral kinetics of ethosuximide were described in terms of a one-compartment open model with first-order elimination (and first-order absorption for oral kinetics). Volume of distribution (overall mean +/- SD=0.80 +/- 0.09 liters/kg), total body clearance (overall mean +/- SD= 19.2 +/- 2.70 ml/hr/kg) and elimination half-life (overall mean +/- SD=28.98+/-3.35 hr and 28.10+/-3.17 hr following intravenous and oral administration, respectively) remained constant over the dosage range Appendix) was selected to describe the disposition of ethosuximide in monkeys. Accordingly, plasma concentrations of individual animals and the average concentrations of Fig. 1 were fitted to a monoexponential equation [Eq. (A1)]. A close agreement between experimental datum points and least-squares fit lines was observed at all three dose levels. Plots of C0 and area under the plasma concentration-time curve [AUC, measured by trapezoidal rule, Eq. (A3)] vs dose (Fig. 4) were linear as predicted by Model I. It may be concluded, therefore, that a one-compartment open model with first-order elimination is appropriate to describe the intravenous kinetic behavior of ethosuximide in monkeys. The volume of distribution (overall mean +/- SD = 0.80 +/- 0.09 liters/kg) observed in the present study is higher than total body water and therefore suggests accumulation of ethosuximide in body tissues. Tissue distribution studies have not been performed in monkeys. However, data on tissue/plasma ratios in rats (Dill et al., 1965; Chang et al., 1972) indicate that ethosuximide can partition outside the total body water compartment. This behavior is compatible with the high pKa value and negligible protein-binding characteristics of ethosuximide (Chang et al., 1972). As discussed by several workers (Levy, 1968; DiSanto and Wagner, 1972; Lockard et al., 1974), the establishment of dose independency in elimination processes (kinetic linearity) requires that single-dose studies be performed at several dose levels. In the dose range examined in the present study (30 to 90 mg/kg), there was no evidence of dose-dependent elimination kinetics after intravenous or oral administration. The overall mean (+/- SD) elimination half-life (28.5 +/- 3.24 hr) obtained in the present study is somewhat longer than the value (22.0 hr) observed by Chang et al. (1972) following a single-dose (100 mg/kg) oral administration of ethosuximide in 4 rhesus monkeys. In view of the agreement between the predictions of Model I and experimental intravenous data, a one-compartment open model with first-order absorption and elimination processes (Model II, Appendix) was studied. The bioavailability of the syrup formulation used in the oral studies was essentially complete (overall mean +/- SD=96% +/- 12.0) and dose-independent...

Administration, Oral↗
PubMed1975

Pharmacokinetic properties of ethosuximide in monkeys. II. Chronic intravenous and oral administration.

Three types of chronic-dosing experiments were implemented in a group of chronically catheterized male rhesus monkeys: Study I, constant rate infusion; Study II, infusion at three consecutive rates with priming doses; and Study III, oral multiple dosing at two consecutive levels with priming doses. Zero-order infusion rates and priming and maintenance doses were calculated for each animal using individual single-dose pharmacokinetic parameters. Ethosuximide was measured in plasma and urine by GLC. Experimental and predicted plasma and urine levels were in good agreement for all three studies. Total body clearance (Studies I and II) and elimination half-life (Studies I, II, and III) were not significantly different from their respective single-dose values. Excretion rate was proportional to infusion rate (Study II) and maintenance dose (Study III). It was established that in the case of ethosuximide in monkey, pharmacokinetic parameters derived from single-dose studies can be used to predict multiple-dosing schedules.

Administration, Oral↗