The bioavailability of cefpodoxime proxetil tablets relative to an oral solution.

The bioavailability of cefpodoxime proxetil tablets relative to an oral solution of cefpodoxime proxetil in a sucrose/alcohol/citric acid vehicle was studied in 11 healthy volunteers in a randomized, crossover study. Fasted subjects took one cefpodoxime proxetil 100 mg tablet or 50 mL of a 2 mg mL-1 cefpodoxime proxetil oral solution on two separate occasions. In a third study period, all subjects took a 100 mg dose of the oral solution with a high-fat meal to investigate the effect of food on cefpodoxime proxetil absorption from the oral solution. Serial blood samples were obtained over a 24 h period, and urine was collected for 48 h after dosing. Cefpodoxime concentrations in plasma and in urine were determined using HPLC methods. The bioavailability of cefpodoxime proxetil tablets relative to the oral solution was 82%, as determined from AUC ratios. There was no difference in the rate of cefpodoxime absorption between dosage forms. Food had no effect on the extent of drug absorption from the oral solution but did result in delayed absorption. These results suggest that complete dissolution of cefpodoxime proxetil is critical for optimal bioavailability.

Effect of timing of food on absorption of cefpodoxime proxetil.

The effect of a high-fat meal and the timing of this meal on the absorption of a 400-mg oral dose of cefpodoxime proxetil was evaluated in 20 healthy, adult, male volunteers in a four-way crossover study. The area under the plasma concentration-time curve, peak plasma concentration, and urinary recovery were significantly greater (P = .0001) after administration of cefpodoxime proxetil tablets with and 2 hours after a meal relative to dosing under fasted conditions or 1 hour before a meal. The time to peak concentration did not differ significantly among treatments, which suggests that food did not affect the rate of drug absorption. These results indicate that absorption of cefpodoxime proxetil is enhanced when tablets are taken with food or shortly after a meal.

Effect of food on absorption of cefpodoxime proxetil oral suspension in adults.

The effect of a high-fat meal on absorption of a 200-mg dose of cefpodoxime proxetil oral suspension was evaluated in 20 healthy, male volunteers in a randomized, two-way crossover study. The concentrations of cefpodoxime in plasma and in urine were determined by sensitive and specific high-performance liquid chromatography methods. The area under the plasma drug concentration-time curve, time to peak concentration, and urinary excretion of cefpodoxime were significantly greater (P < or = 0.05) after administration of cefpodoxime proxetil oral suspension with food than under fasting conditions. However, the difference in the areas under the curve between fed and fasted treatments was only 11%, and application of the two one-sided tests procedure showed bioequivalence between treatments for this parameter. The slight increase in the extent of drug absorption and the slower rate of absorption which results when cefpodoxime proxetil is given with food are unlikely to be of clinical importance.

Pharmacokinetics of cefpodoxime proxetil in healthy young and elderly volunteers.

The influence of age on the pharmacokinetics of cefpodoxime was evaluated in 12 elderly (ages 65-85 years) and 12 weight- and sex-matched young (ages 20-33 years) subjects, each of whom received two cefpodoxime proxetil 200-mg tablets every 12 hours for 14.5 days. Serial blood samples and urine were collected after the first dose on day 1, after the morning dose on day 8, and after the last (morning) dose on day 15. Plasma and urine samples were assayed for cefpodoxime concentrations using HPLC methods. Within each age group, mean pharmacokinetic parameters determined on day 1 were similar to corresponding values on days 8 and 15, indicating that cefpodoxime does not accumulate after twice-daily dosing of cefpodoxime proxetil. Based on this result, parameters were pooled across days in each age group. No significant differences were observed between healthy and elderly volunteers in area under the plasma concentration-time curve for the 12-hour dosing interval, peak plasma concentration, or time to peak concentration. Mean urinary excretion and renal clearance of cefpodoxime were significantly lower in elderly subjects. Differences in renal clearance were attributed to the corresponding age-related reduction that was noted in creatinine clearance values, whereas the lower urinary excretion of cefpodoxime probably reflected slightly reduced systemic drug absorption in the elderly. Differences in these parameters between groups were less than 30%, and were unlikely to be of clinical importance. The data indicate that dose adjustment of cefpodoxime in elderly subjects having normal (age-adjusted) creatinine clearance values is not required.

Pharmacokinetics of the R(-) and S(+) enantiomers of ibuprofen in the serum and synovial fluid of arthritis patients.

Eight patients with arthritis and knee effusions received 13 doses of a single 800-mg ibuprofen tablet every 8 hours. Serum and synovial fluid samples were obtained after the first and last doses and assayed for the R(-) and S(+) enantiomers of ibuprofen by a stereospecific assay. Since only S(+)-ibuprofen inhibits cyclo-oxygenase, a description of the time course of this isomer in synovial fluid is needed for the development of suitable pharmacodynamic models. The isomers were significantly different with respect to peak concentrations and areas under the concentration-time curves (AUC) in synovial fluid levels. No significant accumulation of either isomer was observed in serum or synovial fluid levels between the first and the last doses. The steady-state concentration of both isomers fluctuated less in synovial fluid than in plasma, and the synovial fluid concentrations of the S(+) isomer were about twice that of the R(-) isomer. The mean synovial albumin concentration was about 60% of the serum albumin concentration, and the steady-state isomer AUC values in synovial fluid were significantly correlated with the corresponding serum values after the differences between the two fluids with respect to albumin concentration were corrected. The authors conclude that binding of the isomers to albumin and the serum-synovial fluid albumin ratio controls the steady-state distribution of the ibuprofen isomers into synovial fluid. The ramifications of these findings in the development of satisfactory concentration-response relationships are discussed.

Influence of tretinoin on the percutaneous absorption of minoxidil from an aqueous topical solution.

Nineteen healthy male volunteers completed a three-way, randomized, crossover study to determine the effect of the synthetic retinoid, tretinoin, on percutaneous absorption of minoxidil. Subjects received, for 20 days, twice-daily administrations of 1 ml of an aqueous 2% topical minoxidil solution either alone, with once-daily applications of a 0.05% tretinoin cream, or with once-daily applications of a vehicle control cream. When minoxidil was coadministered with tretinoin cream, minoxidil absorption was increased nearly threefold, compared with a 1.3-fold increase in absorption observed with coadministration of vehicle control cream. Transepidermal water loss measurements, which are sensitive to changes in stratum corneum function, were also significantly increased with tretinoin. No treatment-related changes in stratum corneum thickness were observed on the basis of skin biopsy analysis. The findings indicate that percutaneous minoxidil absorption is enhanced by tretinoin as a result of increased stratum corneum permeability.

Excretion of flurbiprofen into breast milk.

The extent of flurbiprofen's excretion into mature (postcolostrum) breast milk was evaluated in 10 healthy, nursing mothers after administration of a single 100-mg tablet. Samples of milk and blood were subsequently obtained over a 48-hour period and assayed for flurbiprofen by high-performance liquid chromatography. The average peak plasma flurbiprofen concentration, 15 micrograms/ml, occurred at 1.5 hours, and the harmonic mean half-life of the drug was 5.8 hours. The average peak milk concentration of flurbiprofen was 0.09 microgram/ml, and the maximum recovery of the dose in breast milk was only 0.07%.