Terminal Elimination Rate Constant Research Articles

Bioavailability of disopyramide in normal volunteers using unbound concentration.

The pharmacokinetics of disopyramide were determined in 10 healthy volunteers after a 300 mg oral dose and again after a 2 mg/kg i.v. dose. The unbound clearance was 599 ml/min and the unbound renal clearance 310 ml/min. The terminal elimination rate constant of unbound drug was 0.180 h-1 after the i.v. dose and 0.203 h-1 after the oral dose. The absorption rate constant was 0.53(-1) and the maximum peak concentration occurred after 3.2 h. The bioavailability was 0.809 using the area under the unbound plasma concentration time curve. Although a saturable plasma protein binding was found in all subjects the bioavailability using the total concentration, in contrast to theoretical expectations, showed the same value (0.813) as the unbound concentrations.

EFFECT OF VEHICLE AND ROUTE ON CLONAZEPAM LEVELS IN RATS

Clonazepam (CLZ) is a useful anticonvulsant; however, studies using different vehicles and routes have found conflicting results. CLZ levels measured in rats after single dose injections of either intraperitoneal (IP) or subcutaneous (SC) CLZ (1.0 mg/kg) dissolved in either propylene glycol (PG), propylene glycol + 18% ethanol (PGEtOH) or polyethylene glycol (PEG 400) were used to calculate the terminal elimination rate constants (beta), area under the time-concentration curve (AUC) and total clearance (CIT). A two way analysis of variance between route of administration and vehicle showed an effect of route on CIT (P<0.001) which depended on which vehicle was administered. When CLZ was dissolved in PG or PEG 400 the beta and CIT was significantly (P<.05) lower, and the AUC was significantly (P<.05) higher after SC than IP injections. The differences in beta, CIT or AUC between SC and IP injections were not significant when CLZ was dissolved in PGEtOH. SC injections produced more stable and reproducible CLZ levels than IP injections regardless the vehicle used. CLZ injections produce different plasma levels depending on the route and the vehicle used. In order to compare studies of CLZ effects, all of these variables must be considered.

Disposition kinetics of cefamandole during continuous ambulatory peritoneal dialysis.

Cefamandole disposition kinetics were examined in six male subjects with renal impairment who were undergoing continuous ambulatory peritoneal dialysis. Creatinine clearance values ranged from less than 1 to 11 ml/min. Cefamandole was given as a 1-g intravenous dose infused over 30 min. Cefamandole concentrations were determined in serum, urine, and dialysis fluid by a high-performance liquid chromatographic method. The following average parameter values were obtained (range): half-life, 6.1 h (4.6 to 9.7); systemic clearance, 21.9 ml/min (8.4 to 35.5); renal clearance, 11.5 ml/min (0.03 to 22.3); dialysis clearance, 0.92 ml/min (0.7 to 1.3); nonrenal clearance, 12.2 ml/min (2.9 to 27.0); volume of distribution, 0.18 liter/kg (0.09 to 0.25); steady-state volume of distribution, 0.17 liter/kg (0.09 to 0.24). Approximately 5% of the dose was dialyzed (range, 2.8 to 8.3), indicating that there is no need to supplement a dosing regimen of cefamandole due to loss by dialysis. There was a positive correlation between creatinine clearance and the terminal elimination rate constant of cefamandole (r2 = 0.41) and cefamandole renal clearance (r2 = 0.83).

Digoxin-diltiazem interaction: A pharmacokinetic evaluation

The pharmacokinetics of digoxin were studied before and after a 2 week course of diltiazem, 30 mg four times daily, in 7 healthy volunteers. Each subject received an IV dose of digoxin before starting diltiazem and again on day 15 of the study. Diltiazem was continued until all sera and urine were collected. During the control and diltiazem phases, respectively, the terminal elimination rate constants were 0.0231 +/- 0.007 h-1 and 0.0254 +/- 0.007 h-1, the volumes of distribution were 10.5 +/- 3.95 l/kg and 10.2 +/- 3.26 l/kg, and the total body clearances were 3.72 +/- 0.78 ml X min-1 X kg-1 and 4.09 +/- 0.94 ml X min-1 X kg-1. None of these pharmacokinetic parameters of digoxin were significantly different before or during diltiazem administration. Overall, there does not appear to be an interaction between digoxin and diltiazem.

Pharmacokinetics of Diazepam and Nordiazepam in the Cat

The cat has been used extensively as an experimental model for studying the pharmacology of compounds that exhibit CNS activity including diazepam and nordiazepam. However, since little is known about the distribution and elimination of diazepam in this species, the pharmacokinetics of diazepam and nordiazepam were studied in the cat following intravenous doses of 5, 10, and 20 mg/kg of diazepam and 5 and 10 mg/kg of nordiazepam. The disappearance of diazepam and nordiazepam from blood was fitted with classical equations. Theoretical and trapezoidal areas under the curve (AUCth and AUCtr) were calculated. The volumes of distribution (Vdβ) were calculated as model-independent parameters for diazepam and nordiazepam. Intrinsic hepatic clearance, extraction ratio, and tissue binding parameters were also calculated for diazepam. From the observed data, it is apparent that the blood concentrations and the resulting areas under the curves are proportional to the dose of diazepam administered and that the pharmacokinetics of diazepam were linear over the dose range studied. In addition, nordiazepam formed after diazepam administration appeared to be proportional to the dose of diazepam administered. The terminal elimination rate constant of nordiazepam remained constant over the dose range studied. It appears that both diazepam and nordiazepam are highly bound to tissue. The total body clearance of diazepam (4.72 ± 2.45 mL/min/kg) is approximately six times that of nordiazepam (0.85 ± 0.25 mL/min/kg). Approximately 50% of an administered dose of diazepam was biotransformed to nordiazepam in the cat.

Oral Bioavailability and Intravenous Pharmacokinetics of Amrinone in Humans

Fourteen healthy males received two 75-mg doses of amrinone as a single capsule and as an intravenous solution in a single-dose crossover study. The mean (±SD) bioavailability, based on the area under the plasma concentration versus time curves, was 0.93±0.12. The plasma data for these subjects during the intravenous phase was described by an open two-compartment body model with a mean (±SD) apparent First-order terminal elimination rate constant, β, of 0.19±0.06hr–1, which corresponds to a half-life of 3.6hr.

2,4,5,2′,4′,5′-Hexachlorobiphenyl: Distribution, metabolism, and excretion in the dog and the monkey

The tissue distribution, metabolism, and excretion of 2,4,5,2′,4′,5′-hexachlorobiphenyl (2,4,5-HCB) were investigated in beagle dogs and cynomolgus monkeys ( Macacca fascicularis). Following a single iv dose of [ 14C]2,4,5-HCB (0.6 mg/kg), excreta, blood, and tissues were collected at time intervals ranging from 30 min to 15 days for dogs and 2 hr to 90 days for monkeys. The concentration of 2,4,5-HCB and its metabolites was determined in all samples. Elimination of the parent PCB from the blood of both species was biphasic with a terminal phase elimination rate constant of 0.045 day −1 for the dog and 0.015 day −1 for the monkey. By 15 days the dog had excreted 66% of the dose, 63% in the feces, and 3% in the urine. The percentage dose remaining was found largely as parent compound in the adipose tissue (16%), skin (6%), and muscle (2%). By 90 days, the monkey had excreted only 18% of the dose (17% in feces, 1% in urine). Again, the major storage depots for nonexcreted dose were adipose tissue 945%) and skin (5%). In anesthetized dogs, 0.8% of the dose appeared in the bile within 2 hr, while only 0.2% of the dose appeared in the bile of anesthetized monkeys in 2 hr. The monkey excreted a greater percentage of dose as parent compound into the bile than the dog. The data provide evidence that the pharmacokinetic behavior of 2,4,5-HCB in the monkey is similar to that observed in other species. However, the dog is unique from other species in that it can readily eliminate 2,4,5-HCB.

Pharmacokinetics of Rosoxacin in Human Volunteers

Reversed-phase liquid chromatography was used to determine plasma rosoxacin concentrations in normal, healthy males, each of whom received one 300 mg capsule of rosoxacin. The plasma data for each subject were described by an open one-compartment body model with first-order absorption, and the pharmacokinetic parameters were determined. The mean (±SE) apparent first-order terminal elimination rate constant was 0.203 ± 0.015 hr–1(N = 16), the mean apparent volume of distribution was 0.644 ± 0.050 liters/kg, and the mean apparent plasma clearance was 2.08 ± 0.15 ml/min/kg.