Increased systemic availability of loperamide after oral administration of loperamide and loperamide oxide with cotrimoxazole.

1. The effects of concurrent administration of cotrimoxazole on the plasma concentration-time profiles of loperamide and its oxide were investigated in two separate studies in healthy male volunteers. Cotrimoxazole (960 mg, twice daily) was administered for 24 h before and 48 h after an oral dose of loperamide oxide (4 mg) or loperamide (4 mg). 2. Coadministration of cotrimoxazole with loperamide oxide did not alter the tmax, Cmax and AUC of loperamide oxide, whereas the Cmax (0.32 +/- 0.14 ng ml-1 without cotrimoxazole; 0.45 +/- 0.18 ng ml-1 with cotrimoxazole; P < 0.05) and AUC (8.13 +/- 1.91 ng ml-1 h without cotrimoxazole; 12.50 +/- 4.60 ng ml-1 h with cotrimoxazole; P < 0.005) of loperamide were significantly increased. 3. Coadministration of cotrimoxazole with loperamide significantly increased the Cmax (0.74 +/- 0.22 ng ml-1 without cotrimoxazole; 1.49 +/- 0.81 ng ml-1 with cotrimoxazole; P < 0.01) and AUC (13.40 +/- 3.80 ng ml-1 h without cotrimoxazole; 25.30 +/- 11.10 ng ml-1 h with cotrimoxazole; P < 0.005) of loperamide, whilst its tmax and t1/2,z were not significantly altered. 4. The increase in loperamide AUC, following coadministration of either loperamide oxide or loperamide with cotrimoxazole, may be due to reduced first pass metabolism of loperamide.