Bioequivalence evaluation of new megestrol acetate formulations in humans.

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet. The tablets were administered to 24 male subjects in a three-way crossover study, balanced for sequence, with 1 week between administrations. The 40 mg tablets were administered qid at 8 AM, 12 PM, 6 PM, and 10 PM, while the 160 mg tablets were administered once at 8 AM. Plasma samples were collected at appropriate times up to 96 hours after administration and were analyzed for megestrol acetate with a validated high-performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h) the rate of absorption was the same for each of the tablets. Relative to the 40 mg qid dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97% and 118%, respectively.

Diflunisal renal clearance in anesthetized dogs: effect of probenecid, urine flow, and urine pH.

Using conventional clearance technique, the net renal clearance of diflunisal is very low, about 1% of glomerular filtration rate. Although net renal secretion is not demonstrable, probenecid significantly decreased renal clearance of the drug. Also, the renal clearance was increased by increases in urine flow or urinary pH. However, in contrast to acetylsalicylic acid, these effects would be expected to be minor, on the one hand to conserve drug or on the other hand in facilitating drug elimination in cases of overdosage.

Pharmacokinetics of methyldopa in man.

Single doses of methyldopa were administered orally and intravenously as aqueous solutions to 12 healthy volunteers in a crossover study. Serial plasma and urine samples were analyzed specifically for methyldopa and its O-sulfate conjugate. Kinetic analyses of the results indicated that methyldopa disposition could be adequately represented by a two-compartment open model. Renal excretion accounted for about two-thirds of the plasma clearance of methylodopa. Absorption profiles were constructed with the aid of the pharmacokinetic model and contrasted with estimates of absorption which were model-independent. The mean fraction reaching the systemic circulation as methyldopa was estimated to be 0.25 (range 0.08-0.62 for n = 11). Although most of the absorption occurred within the first 5 hours oral administration, a minor component, suggestive of limited enterohepatic circulation, persisted from 9 to 36 hours. O-sulfate conjugation was route-dependent and appeared to be derived predominantly, if not exclusively, as a first-pass effect of absorption and/or enterophepatic circulation.

Serum concentrations of ampicillin and probenecid and ampicillin excretion after repeated oral administration of a pivampicillin-probenecid salt (MK-356).

Twenty male volunteers received oral doses (2100, 1050, and 525 mg) of a pivampicillin-probenecid salt in a 1 to 1 molar ratio (MK-356) at 12 hour intervals. After each dose peak serum concentrations of probenecid were observed 2 hours later than peak concentrations of ampicillin. Following the first dose of MK-356 the apparent elimination rate of ampicillin was dose-dependent and did not follow first order kinetics, as it showed a longer apparent half life after a higher dose. An equal dose of MK-356 administered 12 hours later caused an increase in the peak serum ampicillin level greater than expected from the concentration of ampicillin after the preceding dose. In twelve male volunteers who received at random 525 mg of MK-356 or 350 mg of pivampicillin, each three times daily for 4 days, the areas under the ampicillin concentration curve were the same after the first or last dose of either drug. When 2100 or 1050 mg of MK-356 was taken as an initial dose, 30 to 40 per cent of the ampicillin was recovered from urine in the ensuing 12 hours. The results indicate that when at least 400 mg probenecid was coadministered twice daily with 700 mg pivampicillin (MK-356), the peak serum concentrations of ampicillin were increased and its elimination rate slowed following successive doses.

Physiological disposition and metabolism of 5-(2',4'-difluorophenyl)salicyclic acid, a new salicylate.

5-(2'4'-Difluorophenyl) [carboxy-14C]salicyclic acid (MK-647) was quickly and completely absorbed in rats, dogs, and man. Peak levels of plasma radioactivity occurred in 1-2 hr after oral administration. The dose was 10 mg/kg in rats and dogs, and 50 or 500 mg in man. Most of the drug in plasma was intact MK-647 which was extensively bound to plasma protein. In man the peak concentration following the 500-mg dose was approximately 10 times that after the lower dose, which suggests that absorption rates of both doses were similar. Elimination of drug from plasma was dose-dependent. The area under the curve for MK-647-14C in plasma was 18 times higher following the 500-mg dose than the 50-mg dose. Dogs given 10 mg/kg orally or intravenously excreted 44% of the dose in the urine and 42% in the feces in 72 hr. Rats given the same dose level by either route of administration excreted 80% in the urine and 11% in the feces. In man approximately 95% of a 50- or 500-mg oral dose was excreted in the urine and 3% in the feces, in 96 hr. MK-647 and two metabolites were present in the urine of three species. The ether and ester glucuronides were identified in human urine. The latter metabolite was also identified in rat and dog urine. The glycine conjugate of MK-647 was not observed in the urine of the three species. No interaction was observed between MK-647 and bishydroxycoumarin in the prothrombin time test nor with tolbutamide in the glucose tolerance test. A significant lowering of hexobarbital sleeping time was observed in female, but not male rats after four consecutive daily doses of MK-647. After repeated daily administration of MK-647 (12.5-100 mg/kg), the diurnal plasma level in dogs was not significantly altered, indicating that no saturation, induction, or inhibition of its own metabolism took place.

Evaluation of two new megestrol acetate tablet formulations in humans.

The bioequivalence of two new investigational 160 mg tablets, one containing the regular form and the other a micronized form of megestrol acetate, was determined relative to a commercially available 40 mg tablet (Megace). The tablets were administered to 24 male subjects in a three-way cross-over study, balanced for sequence, with a week between administrations. The 40 mg tablets were administered q.i.d. at 08.00, 12.00, 18.00 and 22.00 h, while the 160 mg tablets were administered once at 08.00 h. Plasma samples were collected at appropriate times out to 96 h after administration and were analysed for megestrol acetate with a validated high performance liquid chromatographic procedure. Based on the times to maximum plasma concentrations (2.5 to 2.8 h), the absorption rate constant was the same for each of the tablets. Relative to the 40 mg q.i.d. dose, the 160 mg regular and the 160 mg micronized tablets had mean relative bioavailabilities of 97 per cent and 118 per cent, respectively.

Effect of sustained release on the pharmacokinetic profile of indomethacin in man.

The effect of sustained release on the pharmacokinetic profile of indomethacin was examined by comparing to three reference regimens: an intravenous dose, a single 75 mg dose of conventional capsules, and three 25 mg conventional doses given at 4-h intervals. Results indicate that the sustained release test formulation exhibited more prolonged and uniform absorption rate, yielded more sustained plasma levels after ingestion, and showed an overall bioavailability of 0.93 (95 per cent C.I. = 0.82, 1.04) relative to three 25 mg doses of the conventional capsules.

Evaluation of succinimidoethyl and pivaloyloxyethyl esters as progenitors of methyldopa in man, rhesus monkey, dog, and rat.

The succinimidoethyl (Sm) and pivaloyloxyethyl (P) esters of methyldopa were evaluated as progenitors of the latter. Experiments in spontaneously hypertensive (SH) rats and humans demonstrated that a radioactive dose of progenitor was well absorbed. The metabolism of these progenitors appeared to be comparable in the SH rat; the urinary excretion of [3H]methyldopa was similar after oral administration of [3H]Sm or [3H]P. In humans the levels of [3H]methyldopa were higher in the urine following administration of [3H]P. Apparently Sm was more resistant than P to extrahepatic esterase action in man (and dog). In man the catechol nucleus of Sm was apparently conjugated prior to hydrolytic cleavage to release conjugated [3H]methyidopa. The progenitors possessed similar antihypertensive properties in the SH rat but preliminary results in humans suggested that Sm possessed less antihypertensive potency than P.

Effects of concomitant aspirin administration on the pharmacokinetics of indomethacin in man.

Ten healthy volunteers each received single and multiple 50-mg doses of indomethacin orally and a single 25-mg dose of [14C]indomethacin intravenously in the absence of and concomitantly with 1200 mg of aspirin as a single dose and in a chronic t.i.d. regimen. Systematic analysis of the data resulted in the isolation and quantification of aspirin's effects on the absorption, distribution, biotransformation, excretion, enterohepatic circulation, and accumulation of indomethacin. The effects of chronic aspirin were to suppress the renal clearance, to increase the biliary clearance, to decrease the efficiency of gastrointestinal absorption, and to enhance the enterohepatic circulation of indomethacin. On concomitant administration of 1200 mg of aspirin t.i.d., mean plasma levels of indomethacin were depressed by 20% after a single oral dose, by a smaller margin after multiple oral doses, and not at all after a single intravenous dose of indomethacin. The mean plasma concentration of orally administered indomethacin was decreased by 8% when given concurrently with a single 1200 mg dose of aspirin. Concomitant chronic therapeutic dosages of indomethacin had no effect on salicylate accumulation from repetitive doses of aspirin.