We examined the alterations in vitamin A metabolism as a result of flupenthixol or cefotiam administration. The impact of these drugs on indices of vitamin A status was evaluated in Brown Norway and Long-Evans rats. Intramuscular drug administration for 28 d resulted in a decline in systemic retinol. Changes in circulating retinol with time for chronic dosing showed drug treatment (P<0.001) and time (P<0.03) to be significant factors, but rat strain (P=0.33) was not a significant factor. Flupenthixol was the most active retinol-lowering compound (P<0.005). At the end of the 28 d period, hepatic retinyl ester hydrolase activity was greater in drug-treated rats than in controls (P<0.05). With regard to effects on liver reserves: (1) flupenthixol treatment resulted in vitamin A depletion (P<0.05); (2) cefotiam treatment stimulated vitamin A accumulation; (3) distinctive patterns of retinol and its esters were seen in response to treatment. It is reasonable to assume that the drugs interfere with vitamin A in at least two ways: (1) lowering of plasma retinol, an early event in the interaction, may be caused by inhibition of hepatic holo-retinol-binding protein secretion or stimulation of clearance, or both; (2) when plasma retinol levels are persistently low, and as the hepatic deposits of the xenobiotics build up, there are changes in the vitamin A pool size and composition of the liver. Candidate enzymes are retinyl ester hydrolase and cytochrome P450. The relationship between these two events will be studied in further detail.