K.S. Albert

Pharmacokinetics of Ibuprofen

The pharmacokinetics of ibuprofen (Motrin) are best described by a two-compartment open model. Ibuprofen pharmacokinetics are only minimally influenced by advanced age, the presence of alcoholic liver disease, or rheumatoid arthritis. Levels of ibuprofen in breast milk are negligible. In addition, ibuprofen can be combined with acetaminophen without altering the pharmacokinetic profile. However, although not yet clinically proved, the concomitant use of ibuprofen and aspirin appears to reduce ibuprofen plasma levels to less than half those observed with ibuprofen alone.

Pharmacokinetics of ibuprofen in man—III: Plasma protein binding

Plasma protein binding of ibuprofen was measured by equilibrium dialysis on 406 plasma samples collected from 15 normal volunteers following doses of 400, 800, and 1200 mg of ibuprofen as tablets (N=102, 100, 104, respectively) and 420 mg as an aqueous solution (N=100). Individual subject bound concentration at dialysis equilibrium (Cbd) vs. free concentration at dialysis equilibrium (Cfd) were well fitted via computer to the Scatchard equation with one class of binding sites. The binding capacity averaged 1231 μM (range 848–1658 μM), and the association constant averaged 1.76 × 105M−1 (range 1.15 × 105 to 2.73 × 105M−1). Distributional analysis was performed on the free fraction (fd) and bound/free ratios (Cbd/Cfd=1/fd−1) at dialysis equilibrium for each treatment. Using pooled data of all four treatments, distributional analysis was also performed on the free fractions (f) and bound/free ratios (Cb/Cf=1/f−1) corresponding to the plasma drug concentrations in blood as it was withdrawn from the subjects. The bound/free ratios were normally distributed, whereas the distributions of the free fractions were skewed towards higher values.

Influence of route of administration on the pharmacokinetics of methylprednisolone

This study was conducted to evaluate the influence of route of administration upon the bioavailability and pharmacokinetics of methylprednisolone sodium succinate. Fourteen healthy adult male volunteers received 40 mg doses of methylprednisolone as the following treatments after an overnight fast in a 4-way crossover design: (a) as a 1 ml i.v. bolus;(b) as a 1 ml i.m. injection;(c) administered as an oral solution;and (d) as 5×8 mg oral tablets. Both the ester and free methylprednisolone were determined in plasma and urine. Study results indicate that the ester is rapidly and extensively converted to free methylprednisolone after all routes. The extent of methylprednisolone absorption was equivalent after i.v. and i.m. administration. Both orally administered treatments resulted in a lower extent of absorption attributed to a first-pass effect. Although a slightly lower extent of absorption was demonstrated following the oral administration of the methylprednisolone sodium succinate solution relative to the methylprednisolone oral tablets, this average difference of 9% would probably be of minimal therapeutic importance.

The Influence of Hemodialysis on the Pharmacokinetics of Ibuprofen and Its Major Metabolites

The pharmacokinetics of ibuprofen and its two major metabolites, the hydroxy and carboxy derivatives, were studied in seven functionally anephric subjects undergoing hemodialysis therapy. Subjects received ibuprofen 800 mg tid for 14 days. Hemodialysis was performed three times weekly during this period. Arterial and venous blood samples were collected before dialysis and along with dialysate, and during the final dosing interval and dialysis session. No accumulation of ibuprofen plasma concentrations and an absence of intact ibuprofen in dialysate indicated clearance through metabolic pathways. The metabolites did accumulate significantly (mean plasma levels, carboxy 249 μg/mL and hydroxy 57 μ/mL); however, both were detected in dialysate. Mean extraction efficiencies were 0.16 (hydroxy) and 0.15 (carboxy). Dialysis clearance calculated by arterial‐venous difference was found to agree with actual recovery in dialysate for both metabolites. Side effects were not observed in any subject.

Ibuprofen Kinetics In Plasma and Synovial Fluid of Arthritic Patients

After administration of a single dose and at steady state, ibuprofen concentrations were measured simultaneously in plasma and synovial fluid obtained from eight patients with rheumatoid arthritis. By seven hours after a dose at steady state, the mean synovial fluid: plasma ibuprofen concentration ratios were constant, and the synovial fluid levels were, on average, greater than those in plasma. The extent to which ibuprofen was bound to protein was somewhat greater in plasma than in synovial fluid. As a result, the mean synovial fluid:plasma free concentration ratio for seven‐hour and later specimens was greater than that based on total concentrations. The degree of accumulation of ibuprofen in each fluid was minimal, consistent with its short half‐life.

Ibuprofen and acetaminophen kinetics when taken concurrently

We evaluated kinetics of ibuprofen and acetaminophen taken concurrently by 20 healthy adults in a randomized crossover design. Steady‐state blood levels of ibuprofen and acetaminophen were measured by gas‐liquid chrornatography and HPLC. There were no significant differences in any of the ibuprofen serum concentrations, but there were differences in acetaminophen serum concentrations in 5 of 19 sampling times. When bioavailability and kinetic parameters for both drugs were compared, there were no significant differences. Our data demonstrate that steady‐state kinetics of ibuprofen and acetaminophen are not changed when taken concurrently.

The effect of food on the bioavailability and pharmacodynamics of tolbutamide in diabetic patients.

SummaryThe effect of food on the rate and extent of absorption of tolbutamide in diabetic patients was studied by varying the time of drug administration in relation to the ingestion of a standard meal. Serum levels of tolbutamide, insulin and glucose and related bioavailability parameters were compared following the administration of a single dose of tolbutamide 0.5 g to diabetic patients 30 min prior to and immediately before a standardized meal. A placebo dosage form was also administered to determine baseline glucose and insulin response to the meal. The 700 calorie standard meal was composed of 41% carbohydrate, 18% protein, and 41% fat. Administration of the drug with the meal resulted in a 6% (statistically significant) decrease in the extent of absorption, as determined by measurement of the area under the tolbutamide serum level-time curve from zero to infinity. Serum levels of tolbutamide were also significantly higher 0.5 h after drug administration when the drug was taken with the meal. Except for these two minor effects, no other differences between the drug treatments were observed in any other parameters of tolbutamide absorption or in the postprandial glucose and insulin serum levels. Therefore, the small differences found were judged to be clinically meaningless. These findings demonstrate that administration of tolbutamide 0.5 g tablets 30 min prior to or with a standard meal results in equivalent therapeutic actions.

Influence of kaolin-pectin suspension on steady-state plasma digoxin levels.

Abstract: The effect of a kaolin—pectin antidiarrheal mixture on steady‐state plasma levels of orally administered digoxin in subjects receiving chronic digoxin therapy was evaluated when the antidiarrheal and the cardiac glycoside were given concomitantly and when two doses of antidiarrheal were given, one 2 hours before and the other 2 hours after digoxin. Although simultaneous administration of both products decreased peak digoxin levels by 36 per cent, 24‐hour areas under the curve were reduced by only 15 per cent, indicative of a slight decrease in digoxin bioavailability. In contrast, when their times of administration were separated by 2 hours, no evidence of a drug interaction was noted. Hence, the effect of one or two doses of kaolin—pectin suspension on steady‐state plasma levels of digoxin appears inconsequential in patients on chronic oral digoxin therapy. Saliva levels were poorly correlated with plasma levels, presumably because of complexation in the oral cavity.

The Effect of Colestipol Hydrochloride on the Bioavailability and Pharmacokinetics of Clofibrate

Since it has been reported by several authors that colestipol HCl and clofibrate have an additive effect in lowering serum cholesterol levels, it was felt advisable to evaluate the blood levels of clofibrate when given simultaneously with colestipol HCl to see whether there was any evidence for drug interaction between the two products that might dictate a need for separation of their administration time. After concomitant single-dose administration, the serum p-chlorophenoxyisobutyric acid levels, bioavailability parameters, and pharmacokinetic parameters investigated provided no evidence for an interaction and suggested that colestipol and clofibrate can be administered concomitantly or at separated in tervals according to whichever dosage regimen is deemed advisable by the physician.

A Low-Resolution Separation of C14 -Glyburide and Its Metabolites from Plasma Extracts Using a High-Performance Liquid Chromatograph Guard Column

Abstract A low-resolution method for simultaneous, rapid determination of radiolabeled glyburide and its metabolites in human plasma is described. Plasma samples were extracted with ethyl acetate. Extracts were redissolved in 300 μl of mobile phase, and injected into a 3 cm guard column, which was incorporated as a loop in a six-port switching valve. C14-glyburide was collected as a single 4-min fraction at a flow rate of 4 ml per min. Following collection of a 1-ml fraction, the column was backflushed with methanol to allow collection of the metabolites of glyburide. The mean value of recovered radioactivity was 95.5 ± 5.7%. The validity of the separation was verified in a high-resolution HPLC system and no cross contamination of the fractions was observed.