Effects of dose and sex on the pharmacokinetics of piroxicam in the rat

Abstract

The effects of dose and sex on the pharmacokinetics of piroxicam were studied in the rat. Piroxicam was administered intravenously at doses of 0.50 and 5.0 mg kg⁻¹ to male and female rats. Plasma drug concentrations were determined by a highly sensitive high‐performance liquid chromatographic technique. Non‐compartmental pharmacokinetic parameters were calculated by area/moment analysis. A prolonged terminal half‐life averaging 13.3 h in male rats and 40.8 h in female rats was observed. Dose had no effect on the disposition of piroxicam. The sex of the rat, however, had a marked effect on piroxicam pharmacokinetics, with mean total clearance differing three‐fold from 0.01841 h⁻¹ kg⁻¹ in male rats to 0.00622 1 h⁻¹ kg⁻¹ in female rats. The free fraction of piroxicam in serum was greater in male rats than in female rats owing to a higher association constant for piroxicam binding to female rat serum proteins. Free piroxicam clearance differed approximately two‐fold with mean values of 0.764 1 h⁻¹ kg⁻¹ and 0.418 1 h⁻¹ kg⁻¹ in male and female rats, respectively. Thus, protein binding partially explained the sex‐dependent disposition of piroxicam. However, sex‐dependent metabolism of the drug also appears to be a major determinant of sex‐related differences in piroxicam pharmacokinetics. Steady‐state volume of distribution was unaffected by sex. Half‐life and mean residence time were three‐fold greater in female rats owing to the three‐fold lower clearance value compared to male rats.