D. K. Sommers

Pharmacokinetics and tolerance of cefuroxime axetil in volunteers during repeated dosing.

A total of 158 volunteers each received 21 repeated oral doses of 500 mg of cefuroxime axetil (CAE) during four comparative cross-over trials. Pharmacokinetics were studied in 8 volunteers (CAE versus ampicillin), relative bioavailability and tolerance were studied in 100 volunteers (CAE versus pivmecillinam and CAE versus pivampicillin), and tolerance alone was studied in 50 volunteers (CAE versus ampicillin). Overall, urinary recoveries of the active antibiotics ranked absorption of the drugs in the order least to greatest: pivmecillinam, ampicillin, CAE, and pivampicillin. The pharmacokinetics of CAE and ampicillin did not change after repeated dosing. Peak serum levels of cefuroxime were significantly higher than those of ampicillin after doses 1 and 21 but the urinary recoveries of both antibiotics were around 35% of the dose. CAE was as well tolerated as ampicillin but there were smaller numbers of episodes of fluid bowel motions on pivmecillinam and pivampicillin than on CAE, which may have been due to the smaller amounts of active antibiotic in the doses of the pivaloyloxymethyl esters.

Pharmacokinetics of ceftazidime in male and female volunteers.

The pharmacokinetic behavior of ceftazidime was assessed after single bolus intravenous injections of 1 g to 12 male and 12 female volunteers. The kinetic handling of the drug was essentially identical in the two sexes, exhibiting two-compartment model characteristics. However, the peripheral compartment volume of distribution of ceftazidime was smaller in the females (mean 3.95 liters, compared with 6.15 liters), and this was attributed to a smaller extracellular fluid volume. Eight volunteers in each group also received single 1-g doses of ceftazidime into the vastus lateralis and gluteus maximus muscles. The time to peak concentration was longer in the women, and it was longer after injection into the gluteus maximus in both sexes, presumably because of differences in local blood flow. The bioavailability of ceftazidime may have been slightly reduced by delays in absorption. Again, body and renal clearances were similar for both sexes when allowance was made for differences in distribution volume.

Lack of bioavailability of mebeverine even after pretreatment with pyridostigmine

AbstractObjective: After the oral administration of mebeverine to animal or human, measurable concentrations of the drug have never been found in the plasma. The ex vivo hydrolysis of mebeverine can be blocked by esterase inhibitors. In the present study, human volunteers were pretreated with pyridostigmine to attempt to improve the bioavailability of the parent drug. Methods: Following a single-blind, random design, 12 normal human volunteers received orally either placebo or 60 mg pyridostigmine, followed 2 h later by 405 mg mebeverine. Blood samples were drawn intermittently for 4 h and were spiked immediately with neostigmine in order to block ex vivo hydrolysis. Results: Even after pretreatment with pyridostigmine, the plasma samples failed to reveal detectable concentrations of mebeverine. Pyridostigmine pretreatment mediated a significantly higher peak concentration of veratric acid, the acid moiety resulting from hydrolysis of mebeverine. Conclusion: As mebeverine seemingly undergoes complete presystemic hydrolysis, it seems unlikely that the effects of the drug could be mediated centrally. Furthermore, as it is unlikely that sufficient mebeverine traverses the intestine to exert a local effect on the colon (i.e., the time-course of veratric acid plasma levels does not support such a conclusion), the therapeutic effect of the drug, if any, has to be ascribed to an active metabolite. However, the hydrolysis products of mebeverine are not known to be pharmacologically active.