In vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome P450 interactions of anidulafungin.

Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of anidulafungin. Experiments included in vitro degradation of anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug's elimination was observed. In conclusion, the primary biotransformation of anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.

The Effect of Urinary pH and Flow Rate on the Renal Elimination of Zopolrestat and Zopolrestat Glucuronide in Humans.

Zopolrestat is an aldose reductase inhibitor that may be useful in the treatment of diabetic complications by reducing flux through the polyol pathway. The plasma half-life of zopolrestat in man is approximately 30 h, and approximately 45% of an orally administered 1000-mg dose is eliminated in the urine as unchanged drug. Because active secretion accounts for much of the renal clearance for zopolrestat, a carboxylic acid with a pK(a) of 5.46, the effect of urinary pH and flow rate on renal clearance of drug was investigated in a series of studies. Renal clearance of zopolrestat following oral administration of 200 mg was determined in normal male volunteers under basal conditions and after treatment with NH(4)Cl and NaHCO(3) to alter urinary pH. Plasma concentrations of zopolrestat were similar under basal and NaHCO(3) treatment but were approximately twofold higher under NH(4)Cl treatment. However, the half-life of zopolrestat under NH(4)Cl treatment (29.5 h) was similar to the half-life of zopolrestat in untreated subjects. Renal clearance decreased by a factor of 2.54 for each unit decrease in urinary pH. In a second study, there was no effect of urine flow rate on renal clearance following an oral dose of 400 mg. Renal elimination of zopolrestat and zopolrestat glucuronide was also examined in volunteers with normal urine flow dosed at either 600 or 1000 mg/day. Whereas renal clearance of zopolrestat decreased with decreasing urinary pH, renal elimination of zopolrestat glucuronide was not affected by pH.

Pharmacokinetics in Non-Insulin-Dependent Diabetics of the Aldose Reductase Inhibitor, Zopolrestat.

The pharmacokinetics of zopolrestat have been examined in non-insulin-dependent diabetic patients after oral administration of a single dose of 1000 mg zopolrestat. T(max) ranged from 2 to 4 h with a mean C(max) of 100 &mgr;g ml(minus sign1). Mean plasma half-life of zopolrestat was 26.9 h. The same patients were also administered oral doses of 1000 mg day(minus sign1) for 10 consecutive days. Mean T(max) was 4.3 h and mean C(max) was 208 &mgr;g ml(minus sign1). Plasma accumulation, the ratio of AUC((0--24)) for the last dose to AUC((0--24)) for the first dose, was 2.67. Apparent oral clearance was 5.71 ml min(minus sign1) and apparent volume of distribution was 12.9 L. The mean urinary excretion of unchanged drug over the 24-h period following the last dose was 36% of the dose while another 7% of the dose appeared in the urine as an acylglucuronide of zopolrestat. Renal clearance of zopolrestat was 1.82 ml min(minus sign1). Binding of zopolrestat to plasma proteins exceeded 99% and was concentration dependent.

Pharmacokinetics and lung tissue concentrations of tulathromycin, a new triamilide antibiotic, in cattle.

The pharmacokinetics of the new triamilide antibiotic tulathromycin was investigated in two cattle studies. Following a single subcutaneous injection, the drug was rapidly absorbed and bioavailability was excellent. High and persistent levels of the drug in lung tissue were observed as well. These attributes are advantageous for an antimicrobial drug indicated for the treatment of bacterial and mycoplasmal respiratory diseases in cattle.