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.

Biological Availability↗

PubMedDate not supplied

Single-dose pharmacokinetics and bioavailability of famotidine in man. Results of multicenter collaborative studies.

Pharmacokinetics and bioavailability of famotidine, a new H2-receptor antagonist, were investigated in healthy subjects in five clinical studies. Linear pharmacokinetics were observed following either intravenous or oral administration. Plasma clearance averaged 463 ml min-1. Renal clearance averaged 310 ml min-1, which exceeded the glomerular filtration rate. Renal excretion was the major route of elimination. Urinary recovery of unchanged drug following intravenous administration was about 67 per cent. Famotidine plasma half-life was approximately 2.6 h. Oral absorption was incomplete. The bioavailability averaged 43 per cent of the dose.

Administration, Oral↗

PubMedDate not supplied

Pharmacokinetics and comparative pharmacology of cefoxitin and cephalosporins.

Features of the distribution, metabolism, elimination, and pharmacokinetics of the cephalosporins and cefoxitin must be considered when concentrations of these drugs in biological fluids are interpreted. The extensive (approximately 86%) binding of cefazolin to plasma protein may account for the smaller volume of distribution and slower rate of renal clearance than are observed for cefoxitin, which is less extensively (73%) bound to protein. Results of microbiological assays of drug in urine may be influenced by the extent of metabolism of the drugs, which is 33% for cephalothin but less than 2% for cefoxitin. Elimination of cephalosporins and cefoxitin occurs by both glomerular filtration and tubular secretion and can be inhibited by the concurrent administration of probenecid. The pharmacokinetics of cefoxitin may be described by a linear, two-compartment, open model that has been used to predict levels of drug achieved in serum and urine after various dose regimens, including administration by intravenous bolus or infusion. The bioavailability of intramuscularly administered cefoxitin is equivalent to that of intravenously administered cefoxitin and is 90% complete within 3-4 hr after the dose is given.

Biological Availability↗

PubMedDate not supplied

Effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats.

The purpose of this study was to examine the effect of enterohepatic circulation on the pharmacokinetics of diflunisal in rats. The "linked animals" experiments provided evidence that diflunisal exhibits an enterohepatic circulation. Within 26 hr after iv administration of diflunisal (10 mg/kg) to rats, excretion was as follows: 42.2% of the dose, bile; 2.3%, unchanged drug; 27.8%, ester glucuronide; and 12.1%, ether glucuronide. On the average, approximately 65% of the amount of the drug and its glucuronides excreted in bile was reabsorbed from the gut. Biliary excretion and plasma data showed that biotransformation of diflunisal to its glucuronides is the rate-limiting step in their elimination. A concentration-dependent decrease in the partial formation clearance to ester glucuronide was observed with decreased concentration of diflunisal. These concentration-dependent kinetics can be at least partly explained by the nonlinear protein binding of diflunisal.

Acylation↗

PubMedDate not supplied

Effect of uremia and anephric state on the pharmacokinetics of sulindac and its metabolites in rats. I. An application of pharmacokinetic model for reversible metabolism.

Plasma levels of sulindac and its metabolites, sulfide and sulfone, were measured in normal, uremic, and anephric rats following concurrent administration of 11C-sulindac and 3H-sulfide (5 mg-eq/kg). A marked decrease in plasma concentration of sulfide was found in uremic rats, while sulindac concentration in these rats was unchanged. In contrast, anephric rats cleared sulindac more slowly than control rats, but had no effect on the sulfide. A pharmacokinetic model for reversible metabolism was used to characterize the kinetic parameters for sulindac----sulfide interconversion system. The intrinsic clearances of unbound drug were calculated for the interconversion and elimination processes. The results indicated that the reduction of sulindac to sulfide is impaired in uremic and anephric rats. The oxidation of sulfide to sulindac was increased in uremic rats, but decreased in anephric rats. Experimental uremia caused a decrease in plasma protein binding of sulindac and sulfide and an increase in the apparent volumes of distribution of the redox species. Anephric state has less effect on plasma protein binding and volume distribution.

Animals↗

PubMedDate not supplied

Effect of uremia and anephric state on the pharmacokinetics of sulindac and its metabolites in rats. II. Differential effects on the biliary excretion.

The differential effects of experimental uremia and surgical anephric state on the biliary excretion of sulindac and its metabolites in rats were investigated. After concurrent administration of 14C-sulindac and 3H-sulfide (5 mg-eq/kg iv), the apparent biliary clearance of sulindac was significantly decreased in anephric rats relative to control rats, whereas the apparent biliary clearance of sulfide was increased in uremic rats as compared to that in control rats. There was a strong positive correlation between the irreversible elimination of sulindac (CLox) and the apparent biliary clearance (r = 0.942). Similarly, the irreversible elimination of sulfide (CLide) was positively correlated with the apparent biliary clearance of sulfide (r = 0.961). A partial explanation is thus provided for differences in the respective effects of uremic and anephric state upon observed CLox and CLide.

Animals↗

PubMedDate not supplied

Comparative effects of H2-receptor antagonists on drug interaction in rats.

The most widely used H2-receptor antagonist, cimetidine, is known to interact with cytochrome P-450 drug-metabolizing enzymes and, therefore, interacts with other drugs which may be administered concurrently. In this study, effects of three H2-receptor antagonists, famotidine, ranitidine, and L-643,441, on drug interaction were studied using cimetidine as a positive control. Cimetidine and L-643,441, but not famotidine or ranitidine, prolonged antipyrine elimination and hexobarbital-induced sleeping time. The effect of cimetidine and famotidine on the anticoagulant effect on warfarin in rats was also investigated. Pretreatment of rats with cimetidine produced a significant depression of plasma prothrombin complex activity, whereas concomitant administration of famotidine did not alter the plasma prothrombin complex activity. Whereas cimetidine is known to impair the elimination of a number of drugs metabolized by microsomal mixed function oxidase enzyme systems, the results of the present study suggest that famotidine and ranitidine have little effect on these enzyme systems.

Animals↗