Prevention of chlorphentermine-induced pulmonary phospholipidosis in rats by phenobarbital.

It has been shown previously that the induction of pulmonary phospholipidosis in rats by chlorphentermine (CP) is essentially prevented by the concurrent administration of phenobarbital (PB). This study was conducted to investigate the mechanism(s) responsible for this protection. Male Long-Evans hooded rats received either 14C-CP (30 mg/kg, ip) or both PB (30 mg/kg, po) and the 14C-CP daily for up to 1 week. Associated with the PB-induced prevention of phospholipid accumulation in the lungs was an 84% reduction in CP content in the tissue. Excretion in urine and feces was 55 and 6%, respectively, of the administered 14C for the CP group, and 66 and 11%, respectively, for the CP + PB group. Increased urinary excretion was not due to enhanced glomerular filtration or urine output. With each group, nearly 80% of the 14C was extracted into ether from alkalinized urine and co-chromatographed on TLC with pure CP. The difference in nonextractable 14C (presumably polar metabolites of CP) between the two groups is small and cannot account for the difference in total 14C excreted in the urine. All of the fecal 14C was CP. These experiments rule out an increase in CP metabolism as the primary basis for the CP-induced enhancement in 14C excretion. PB appears to actually protect against CP-induced pulmonary phospholipidosis rather than reversing it. This occurs by an enhancement in excretion of CP, thereby preventing it from reaching levels in the lungs which lead to PL accumulation.