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Biomedical subjects

I H Patel

Publications and source records attributed to I H Patel.

At least 55 records · Page 3Linked to original sources
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

Pharmacokinetics and tolerance of ceftriaxone in humans after single-dose intramuscular administration in water and lidocaine diluents.

The effects of 1% lidocaine as a diluent on the pharmacokinetics and tolerance of ceftriaxone administered intramuscularly were investigated in 12 adult volunteers. Each subject received two 0.5-g doses of ceftriaxone (one in water and the other in 1% lidocaine) at least 1 week apart in a randomized crossover fashion. Plasma and urine samples were collected serially and assayed for ceftriaxone content by high-performance liquid chromatography. The mean peak plasma concentration, time to attain the peak, area under the plasma curve from time zero to infinity, and elimination half-life were 45 micrograms/ml, 2.5 h, 578 micrograms . h/ml, and 7.1 h, respectively, after intramuscular administration of ceftriaxone in water diluent. The corresponding mean values in 1% lidocaine diluent were 42 micrograms/ml, 3 h, 577 micrograms . h/ml, and 7.0 h. The pharmacokinetic data suggested that 1% lidocaine does not alter either the elimination parameters or the bioavailability of intramuscularly administered ceftriaxone. The intensity and frequency of pain at the injection site were reduced considerably by the coadministered lidocaine.

Adult↗
PubMed1982

Pharmacokinetic characteristics of intravenous ceftriaxone in normal adults.

The multiple-dose pharmacokinetics and tolerance of intravenous ceftriaxone were investigated in 44 adults with normal renal function. Doses of 0.5, 1.0, and 2.0 g every 12 h and 2 g every 24 h were administered intravenously at a constant rate over 30 min. Plasma and urine samples were collected after the first (day 1) and last (day 4) dose and assayed for ceftriaxone by high-pressure liquid chromatography. Considering all four doses, mean peak plasma concentrations ranged from 79 to 255 micrograms/ml on day 1 and from 101 to 280 micrograms/ml on day 4. Trough concentrations at 12 h on day 1 were 15 to 45 micrograms/ml and 20 to 59 micrograms/ml on day 4. After a dose regimen of 2 g every 24 h, trough levels were still in the clinically therapeutic range (13 to 15 microgram/ml). The mean beta-phase t1/2 was markedly long (6.3 to 6.9 h) and was independent of dose. The fraction of dose excreted unchanged in the urine (0.33 to 0.44) indicated a substantial nonrenal mechanism of elimination. The plasma clearance ranged between 1,002 and 1,449 ml/h, and renal clearance ranged from 353 to 529 ml/h. The apparent volume of distribution varied from 9.2 to 13.5 liters. The dose-related increases in calculated Vd and Clp could be attributed to concentration-dependent plasma protein binding because of a larger free fraction of drug at higher concentrations. The drug was well tolerated, and no significant clinical or laboratory abnormalities were noted.

Adult↗
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

Pharmacokinetics of ceftriaxone in humans.

Pharmacokinetics of the investigational cephalosporin ceftriaxone were studied after 30-min intravenous infusions of three ascending single doses of 0.5, 1, and 2 g crossed over in 12 normal subjects. Serially collected plasma and urine samples were analyzed for ceftriaxone by high-performance liquid chromatography. Plasma concentration-time profiles were characterized by a linear two-compartment open model with the following respective mean (+/- standard deviation) parameters at 0.5-, 1-, and 2-g dose levels: elimination half-life, 6.5 +/- 0.7, 6.2 +/- 0.8, and 5.9 +/- 0.7 h; apparent volume of distribution, 8.5 +/- 1.1, 9.0 +/- 1.1, and 10.1 +/- 1.0 liters; and plasma clearance, 929 +/- 150, 1,007 +/- 130, and 1,190 +/- 150 ml/h. The respective renal excretion parameters were as follows: renal clearance, 373 +/- 60, 399 +/- 50, and 533 +/- 128 ml/h; and percentage of dose excreted unchanged in the 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explainhe 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explainhe 48-h urine samples, 41 +/- 8, 39 +/- 5, and 43 +/- 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explained by the concentration-dependent plasma protein binding of ceftriaxone in humans. The impact of the small dose-dependent changes in the pharmacokinetics of ceftriaxone is anticipated to be of negligible clinical significance.

Adult↗
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↗
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

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↗
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↗