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Biomedical subjects

W A Colburn

Publications and source records attributed to W A Colburn.

At least 91 records · Page 5Linked to original sources
PubMed1982

Propoxyphene and norpropoxyphene kinetics after single and repeated doses of propoxyphene.

Plasma concentrations of propoxyphene (P) and its pharmacologically active metabolite norpropoxyphene (NP) were determined in normal subjects after single 130-mg oral doses and during and after 13 consecutive oral doses of 130 mg P, and in former heroin addicts who were maintained on 900 to 1200 mg of P per day. The data were analyzed using a first-pass elimination pharmacokinetic model. Both P and NP cumulated during repeated dosing to levels 5 to 7 times those after the first dose. In contrast, "maintenance" patients exhibited steady-state trough plasma NP cumulation that exceeded that of P by a factor of 13. Several changes in P and NP kinetics occurred during repeated dosing with P to the normal subjects: P clearance decreased from 994 to 508 ml/min, NP clearance decreased from 454 to 2210 ml/min, P half-life (t 1/2) increased from 3.3 to 11.8 hr, NP t 1/2 increased from 6.1 to 39.2 hr, and area under the concentration time curves for P and NP were doubled. These changes in kinetics during repeated dosing resulted in more extensive cumulation of P and NP than would be predicted from the single-dose kinetic profile. Changes in the extent of first-pass elimination of P result in variability in plasma P and NP that may contribute to P-induced toxicity.

Adult↗
PubMed1981

A preliminary report on the pharmacokinetics of saccharin in man: single oral dose administration.

The pharmacokinetics of saccharin were studied in two human subjects. One male and one female subject ingested a single 100 mg oral dose of saccharin. Absorption was fast and the elimination half-lives were 1.2 and 6.6 hours for the male and female subject, respectively. Approximately 85% of the oral dose was recovered in the urine as intact saccharin and renal clearance approximated renal plasma flow when corrected for the unbound fraction of saccharin in plasma. Saccharin elimination appears to be related to previous saccharin ingestion, suggesting a high-retention compartment.

Administration, Oral↗
PubMed1981

Simultaneous pharmacokinetic and pharmacodynamic modeling.

The compartmental model approach previously proposed by Sheiner et al. for the simultaneous characterization of the pharmacokinetics and pharmacodynamics of a drug substance has been rigorously tested and extended in the present report. Pharmacokinetic and pharmacodynamic equations were derived for several commonly used models, as well as alternate models that relate effect to drug concentrations in a peripheral compartment. The versatility and flexibility of these models were tested using simulation and curve-fitting procedures. The utility as well as the limitations of this modeling procedure are discussed.

Animals↗
PubMed1981

Dietary saccharin kinetics.

Six adult female subjects who use saccharin-containing products in their diet were asked to take divided equal doses of saccharin every 6 hr to maintain their average daily intake for 3 days. At the end of this period, each subject took a single dose that was equal to one divided dose. Saccharin concentrations in plasma and urine samples were used to assess the kinetic profile. Saccharin absorption was rapid with maximum concentrations in plasma in 0.5 to 1.0 hr. Maximum plasma concentrations and areas under the plasma concentration-time curves were proportional to dose. Renal clearance exceeded glomerular filtration rate in all cases and approximated renal plasma flow when corrected for the saccharin free fraction in plasma. Mean elimination half-life was 7.5 hr and mean apparent volume of distribution was 264 l. The kinetic parameters indicate that saccharin is distributed as a function of lean rather than total body mass (suggesting that saccharin does not distribute into body fat). This observation, together with data from studies in animals, suggests that there may be one or more high-retention compartments for saccharin.

Adipose Tissue↗
PubMed1981

A new radioimmunoassay for haloperidol: direct measurement of serum and striatal concentrations.

A sensitive and specific radioimmunoassay for haloperidol has been developed. Antibodies were elicited in rabbits immunized with haloperidol hemisuccinate coupled to bovine serum albumin. Optimum sensitivity was obtained with a 1:4000 dilution of the antisera, permitting the detection of as little as 2.6 ng/ml of haloperidol. Major metabolites of haloperidol did not cross-react in the assay. The method does not require an extraction procedure and can be performed using as little as a 5-microliter sample. Haloperidol levels in rat serum and striatum were determined with this method, after the i.v. administration of different dosages of the drug. The distribution and elimination of haloperidol was linear over the dose range to have an elimination half-life of approximately 2.6 hr at all three dosage levels.

Animals↗
PubMed1980

Pharmacokinetic interpretation of plasma cortisol and cortisone concentrations following a signle oral administration of cortisone acetate to human subjects.

The pharmacokinetic and biopharmaceutic profiles of a single dose of oral cortisone acetate were developed for 23 healthy normal adult volunteers using cortisone and cortisol plasma concentration data. Cortisone acetate was rapidly absorbed and converted to the therapeutic moiety cortisol. There was a linear increase in plasma concentrations and, therefore, areas under plasma concentration-time curves with increasing doses of 5, 10, and 25 mg. Twenty-five-mg doses given as 1 x 25 mg or 5 x 5 mg were found to be bioequivalent. The increased efficacy of oral over intramuscular cortisone acetate can be attributed to the increased conversion to cortisol as a result of first-pass metabolism following oral dosing.

Administration, Oral↗
PubMed1980

Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam.

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03-mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03 mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half-life (t1/2) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t1/2 by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration-time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding.

Adult↗
PubMed1980

Renal clearance of salicylic acid and salicyluric acid in the rat and in the isolated perfused rat kidney.

The renal clearance of salicylate (SA) and salicyluric acid (SU) was studied after i.v. bolus injection of 5 mg/kg of SA to ureter cannulated rats and after administration of 1 to 20 mg of SA or 2.5 to 10 mg of SU to the isolated perfused rat kidney. Previous studies in this laboratory have shown that SA and SU are metabolically interconverted in the isolated perfused rat kidney. The renal clearance of SU was greater than the glomerular filtration rate after either SA or SU administration. SA renal clearance was much less than the glomerular filtration rate when SA was administered but was greater than the glomerular filtration rate when it was formed from SU. The data support the hypothesis that administered SA is cleared differently than SA formed from SU in the isolated perfused rat kidney, presumably due to rate-limiting diffusion of SA into the cell.

Animals↗
PubMed1979

Time course of carbamazepine self-induction.

Carbamazepine concentrations in plasma during repetitive oral dosing were analyzed by means of a nonlinear, variable parameter, regression program (VARPARM) assuming dose-to-dose changes in the apparent elimination rate constant of the drug. There was evidence of significant self-induction of carbamazepine metabolism as early as 1 or 2 days after initiation of the multiple-dose study. Additional self-induction appears to occur after about 2 weeks of treatment. The time course of carbamazepine self-induction appears to be complex, discontinuous, and prolonged.

Carbamazepine↗
PubMed1979

A pharmacokinetic model to differentiate preabsorptive, gut epithelial, and hepatic first-pass metabolism.

A combined perfusion/compartmental pharmacokinetic model has been developed to describe the time course of drugs that are subject to preabsorptive, intestinal epithelial, and hepatic first-pass metabolism. Equations are derived to estimate the fraction of the administered dose which is metabolized at each of the three sites and to establish the limits of the true absorption rate constant. The model is tested using literature data for phenacetin.

Biotransformation↗