Sanfetrinem and sanfetrinem-cilexetil: disposition in rat and dog

1. The absorption, distribution, metabolism and excretion of sanfetrinem have been investigated in the rat and dog after intravenous (i.v.) administration of the radiolabelled parent compound, and oral dosing of the hexetil ester prodrug, 14C-sanfetrinem-cilexetil. 2. Sanfetrinem-cilexetil was rapidly absorbed and hydrolysed pre-systemically to sanfetrinem. The oral bioavailability was 32% in rat and 15% in dog. 3. Drug-related radioactivity was distributed in all tissues with high levels present in bladder, kidney and liver. The volume of distribution was approximately that of extracellular fluid. There was no indication of any significant binding or retention to any tissues, including those containing melanin. 4. Protein binding of sanfetrinem determined in rat and dog plasma was constant over a wide range of concentrations equivalent to 14-18% in dog and about 67% in rat plasma. 5. Two metabolites were identified in urine after i.v. administration: the open beta-lactam ring derivative (GV173923) and the dimeric compound (GV196359). 6. After i.v. dosing the terminal half-life of the unchanged drug was 12 min in rat and 35 min in dog. The half-life of the total radioactivity was longer due to low levels of metabolites. Of the dose, > 90% was excreted in the urine both in rat and dog, and 69% of the dose was excreted as unchanged sanfetrinem in rat urine. The radioactivity excreted in the bile accounted for 3-7% of the dose.