FORMATION AND PHARMACOKINETICS OF THE ACTIVE-DRUG CANDOXATRILAT IN MOUSE, RAT, RABBIT, DOG AND MAN FOLLOWING ADMINISTRATION OF THE PRODRUG CANDOXATRIL

1. Candoxatrilat, an active neutral endopeptidase inhibitor, was relea sed rapidly from the inactive prodrug candoxatril in vivo in mouse, ra t, rabbit, dog and man. 2. Oral doses of [C-14]-candoxatril were clear ed rapidly, costly by eater hydrolysis to candoxatrilat, in mouse, dog and man. A complementary intravenous study in man with [C-14]-candoxa trilat showed that the active drug was virtually completely renally cl eared. Neither candoxatril nor candoxatrilat underwent chiral inversio n in man. 3. Systemic availability of candoxatrilat from the oral prod rug was estimated to be 88, 53, 42, 17 and 32%, in mouse, rat, rabbit, dog and man respectively. Plasma clearance of candoxatril was too rap id to enable pharmacokinetic parameter calculation in mouse and rabbit ; fdr man, the apparent oral clearance was 57.9 ml/min/kg and the elim ination half-life was 0.46 h. 4. For intravenous candoxatrilat, total plasma clearance values were 32, 15, 5.5, 5.8 and 1.9 ml/min/kg for mo use, rat, rabbit, dog and man respectively. Renal clearance values wer e 8.7, 7.2, 2.9 and 1.7 ml/min/kg for mouse, rat, dog and man and thes e approximate to the respective glomerular filtration rates. Allometri c scaling with respect to bodyweight across the species allowed reason able prediction of the above two clearance parameters in man.