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W A Colburn

Publications and source records attributed to W A Colburn.

137 records · Page 8Linked to original sources
PubMedDate not supplied

Prolonged impairment of the plasma-protein binding of phenytoin in the rat after a single dose of sodium oleate.

The plasma-protein binding of phenytoin in rats was impaired for more than 14 days after a single injection of sodium oleate compared to that observed in saline-treated controls. A maximum free (unbound) phenytoin fraction value of about 0.30 was found between 30 and 120 min after oleate administration. The free fraction decreased to about 0.20 after 14 days. The free fraction of phenytoin in control rats was essentially constant over this period and averaged about 0.17. The impaired plasma-protein binding of phenytoin was unaffected by prolonged dialysis but was effectively reversed by charcoal treatment of the plasma. Comparison of the in vivo and in vitro effects of sodium oleate on phenytoin binding in plasma indicates that the reduction in binding is unrelated to the in vivo oleate concentration in plasma at the time of the binding determination. For example, 5 min after a bolus injection of oleate, the plasma free fraction of phenytoin was about 0.33. A comparable concentration of oleate in control plasma resulted in a free phenytoin fraction of only 0.21.

Animals↗
PubMedDate not supplied

A pharmacokinetic model for enterohepatic recirculation in the rat: phenolphthalein, a model drug.

A classical compartmental pharmacokinetic model was developed to describe the systemic blood concentration-time profile of phenolphthalein and its glucuronide conjugate (total 3H) following a single intravenous bolus injection of [3H]phenolphthalein. The model incorporates a biliary transport system, including a finite lag time for the biliary phenophthalein glucuronide to be hydrolyzed in the intestine before absorption. Data obtained from bile duct-cannulated animals were fit to the same model excluding any component for intestinal absorption. Agreement between the rate constants obtained for both fits indicates that the model is internally consistent. The model was then used to simulate a 24-hour time-course of phenolphthalein-equivalent blood concentrations which indicates that the long apparent half-lives calculated during this period are artifacts of recirculation.

Animals↗
PubMedDate not supplied

Pharmacokinetics of saccharin in the rat. Renal clearance in vivo and in the isolated perfused kidney.

Saccharin is not metabolized and is rapidly eliminated in urine of the rat. Factors that affect renal excretion, i.e., protein binding, glomerular filtration rate (GFR), and tubular secretion, would thus be important in determining saccharin clearance. The renal clearance of saccharin in the ureter-cannulated rat and in the isolated perfused rat kidney (IPK) were studies after the administration of saccharin in doses of 0.02, 1, or 100 mg/kg. Binding of saccharin in rat plasma and perfusate was variable and insensitive to changes in concentration. The mean free fraction was approximately 0.70 in rat plasma and 0.40 in perfusate. Renal clearances were relatively constant, with a mean of 2.2 ml/min in vivo and 1.9 ml/min in the IPK. Saccharin clearance was consistently higher than the GFR, supporting involvement of tubular secretion in the renal elimination of saccharin. Correlation of data from IPK experiments with the data from in vivo experiments substantiate the utility of this preparation for studying the renal excretion of drugs.

Animals↗
PubMedDate not supplied

Metabolism of salicylic acid in the isolated perfused rat kidney. Interconversion of salicyluric and salicyclic acids.

Renal metabolism of salicylic acid (SA) to salicyluric acid (SU), as well as the metabolism of SU to SA, was demonstrated in the isolated perfused rat kidney. SU formation was dependent upon the inclusion of a glycine pool and glycine concentration influenced the rate of SU excretion. The total conversion of SA to SU in 1 hr was 7.7% after the administration of 1 mg SA. Administration of increasing amounts of SA diminished this extent of SU formation. The addition of a competitive substrate, benzoic acid, produced a rapid formation and excretion of hippuric acid with a corresponding inhibition of SU formation and excretion. It is important to note that when isolated kidneys were perfused with 2.5 mg SU, 20--30% of the dose was metabolized to SA. Increasing the dose of SU to 10 mg decreased the amount of SA formed. In view of observed reversible SA/SU metabolism, a larger renal contribution to overall salicylate disposition is suggested.

Animals↗
PubMedDate not supplied

Renal clearance of carprofen in the isolated perfused rat kidney.

The renal clearance of the anti-inflammatory agent, carprofen, was studied in the isolated perfused rat kidney (IPK). The dosing range used (0.5-25 mg) produced perfusate concentrations comparable to and greater than therapeutic plasma concentrations expected in man. In vitro studies in the rat were done as a basis for comparison to the in vitro IPK parameters. Because of its extensive binding (greater than 99%) to the protein fraction of the perfusate, the urinary excretion of carprofen was low an perfusate concentration-dependent. The calculation of the tubular transit rate at each carprofen concentration indicated the following net mechanism(s) of renal carprofen clearance: filtration at low concentration, reabsorption at intermediate concentrations, and secretion at the highest concentration. At low urinary pH and flow rates, reabsorption effectively counteracted secretion. The present in vitro studies suggest that carprofen is excreted by the kidney by the pathway common to a variety of organic acids.

Animals↗
PubMedDate not supplied

Role of gut contents, intestinal wall, and liver on the first pass metabolism and absolute bioavailability of isotretinoin in the dog.

The absolute bioavailability and first pass metabolism of isotretinoin by the gut contents, gut wall, and liver of the dog were assessed with a sensitive and specific high performance liquid chromatographic analytical method and a recently published pharmacokinetic model. [12C]- and [14C]isotretinoin were simultaneously administered to the dog by iv and oral routes, respectively. Blood samples were obtained from the jugular and the portal veins at specified times to quantify [12C]isotretinoin and [14C]isotretinoin blood concentrations. In addition, blood, bile, urine, and the gastrointestinal contents were analyzed for carbon-14-containing materials. The harmonic mean elimination half-life (t 1/2 beta) for the simultaneous iv and oral administration was approximately 5.5 hr. The mean +/- SD blood clearance (ClB) following iv administration and the intrinsic clearance following oral administration were 5.19 +/- 2.40 and 6.63 +/- 3.72 ml/min/kg, respectively. The average absolute bioavailability was 21%, indicating an overall first pass effect of approximately 80%. The majority (approximately 72%) of the first pass effect occurred in the gut lumen with the gut wall and liver making a lesser contribution to the overall first pass effect. These results demonstrated that the low absolute bioavailability was largely due to loss of drug prior to reaching the portal circulation; and analysis of gut contents for total carbon-14 activity suggested that a fraction of isotretinoin dose was biologically or chemically degraded in the gut lumen prior to absorption.

Animals↗
PubMedDate not supplied

Effect of route of administration and biliary excretion on the pharmacokinetics of isotretinoin in the dog.

Oral, intraportal, iv doses of isotretinoin were administered to dogs before and after bile duct cannulation to determine the effect of route of administration and biliary excretion on the pharmacokinetics of this compound. Blood and bile samples were collected and analyzed for isotretinoin using a gradient elution high performance liquid chromatographic method. Blood concentrations were decreased after bile duct cannulation. Decreases in the area under the blood concentration-time curves were greatest following oral dosing, intermediate following intraportal dosing, and least following iv dosing. These results indicate that biliary excretion impacts on the blood profile of isotretinoin as a function of route of administration and that the differences are the result of differences in first pass clearance. In addition, the apparent bioavailability of isotretinoin was 14% in bile cannulated dogs and 54% in the intact (uncannulated) animals, suggesting that enterohepatic recycling of isotretinoin may contribute to its oral bioavailability. Isotretinoin was excreted in the bile; predominantly as a conjugate. The largest percentage (approximately 27%) of the dose was excreted in the bile following intraportal infusion, an intermediate percentage (approximately 8.5%) after iv dosing, and the smallest percentage (approximately 3.3%) after oral dosing. When the amount of drug excreted in bile as intact drug and conjugate is divided by the area under the systemic blood concentration--time curve, the resulting apparent biliary clearances following oral and intraportal administration were almost identical whereas the apparent biliary clearance after iv dosing was substantially less.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMedDate not supplied

Influence of protein binding and metabolic interconversion on the disposition of sulfisoxazole and its N4-acetyl metabolite by the isolated perfused rat kidney.

The renal clearances of sulfisoxazole (SX) and N4-acetylsulfisoxazole (NSX) were studied in the isolated perfused rat kidney (IPK). Studies were conducted with conventional bovine serum albumin perfusates as well as with dextran perfusates to assess the influence of perfusate protein binding on the disposition of these compounds by the IPK. The results presented herein indicate that the disposition of sulfisoxazole by the IPK involves both metabolism and excretion. The metabolism of SX to NSX is reversible and is influenced by protein binding since metabolism increased with increased free fraction (Ff). The excretion of SX and NSX reflects a complex interaction of filtration, secretion, and reabsorption. A comparison of clearance values between kidneys perfused with bovine serum albumin perfusate (Ff 0.1) and dextran perfusate (Ff 1.0) suggests that tubular secretion of SX is a function of total (unbound plus bound) rather than free (unbound) drug in the perfusate.

Acetylation↗