Enzymatic retinyl ester hydrolysis is a key reaction for maintaining cellular retinol homeostasis. The ability of naftidrofuryl and erythromycin to inhibit retinol liberation by retinyl ester hydrolase (REH) in vitro suggests an ability to interfere with vitamin A metabolism in vivo, particularly during hepatic processing. To address this question, systemic and local response to these agents were studied in Brown Norway (BN) and Long-Evans (LE) rats. The study was conducted in two parts: a drug-loading phase and a washout phase. Analysis of variance of the time course changes in plasma retinol during the post-treatment period (Days 10-18) showed rat strain (p < 0.04) and time (p < 0.001; strain-by-time interactive effect, p < 0.001) to be significant factors, but drug exposure (p = 0.19) was not significant. Endpoints included hepatic REH activity, size and composition of the liver vitamin A stores, and retinoid content of the kidneys. Rats recovering from naftidrofuryl dosing demonstrated a lower REH activity than did animals recovering from erythromycin treatment (p < 0.009). The major side effect of erythromycin is vitamin A accumulation in the liver (p < 0.001) and reductions in retinol reserves (p < 0.02) were among the consequences of naftidrofuryl treatment. In the kidney of LE rats, there were higher concentrations of vitamin A (p < 0.003) secondary to naftidrofuryl exposure. Together our data suggest that clinically achievable concentrations of the drugs, given as a continuous infusion, produce aberrations in vitamin A metabolism.

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 (P¼0·33) 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. Flupenthixol -vitamin A interaction: Cefotiam -vitamin A interaction: Retinyl ester hydrolase

Amiodarone, an antiarrhythmic drug, and trimeprazine, an antipsychotic drug, are both in vitro inhibitors of retinyl ester hydrolase. To determine whether these agents have deleterious effects on aspects of vitamin A metabolism, Brown Norway rats (n 18) were treated at clinically equivalent doses once daily for 26 d with either oral drug. On day 27, a tolerance test was used to determine whether these agents interfered with vitamin absorption. During the first 8 d, the plasma retinol level declined in all animals. Between days 12 and 27, it rose to near pre-treatment concentrations in the control and trimeprazine groups and remained relatively constant at low levels (P,0·001) in the amiodarone group. The intestinal absorption of vitamin A was reduced (P,0·05) in the amiodarone group compared with the placebo and trimeprazine groups, which did not differ significantly from each other. At the end of the 4-week treatment period, hepatic retinyl ester hydrolase activity was lower in the drug-dosed rats (P¼ 0·06 for amiodarone) than in the controls. With regard to effects on liver reserves, drug treatment resulted in vitamin A depletion (P,0·019), and distinctive patterns of retinol and its esters were seen in response to dosing. In conclusion, amiodarone and trimeprazine have been shown to influence different aspects of retinoid metabolism, namely absorption, storage and transport. In clinical practice, the routine unmonitored use of these drugs and the suggestion that these agents be taken with meals are not recommended. Amiodarone-vitamin A interaction: Trimeprazine -vitamin A interaction: Retinyl ester hydrolaseVitamin A is a fat-soluble vitamin present in animal-based diets as retinyl esters (retinol esterified to fatty acids; Schindler et al. 1987). Once absorbed, liberated retinol is converted by the activity of acyltransferase back to esterified retinol, in which form vitamin A is targeted to the liver, its primary site of storage MacDonald & Ong, 1988). Central to vitamin A handling by the organism is the reversible, enzymatic conversion of retinyl esters to retinol (for reviews see Harrison, 1998).Retinyl ester-splitting enzymes are found ubiquitously, in many tissues, and it is generally assumed that their function, activity and regulation depend on the enzyme location. Whereas retinolliberating enzymes from pancreas and intestinal brush border are a pre-requisite for the full absorption of dietary vitamin A (Lombardo & Guy, 1980;Rigtrup et al. 1994), isoenzymes in eyes provide free retinol as an intermediate in rhodopsin regeneration (Tsin & Lam, 1986). In the liver, the central organ in maintaining body retinol homeostasis, the retinyl ester-converting enzymes are involved in the hydrolysis of vitamin A esters delivered to the hepatocytes via the receptor-mediated endocytosis of chylomicron remnants (Blomhoff et al. 1982) and the generation of free retinol from its storage form as esters (Goodman & Blaner, 1984). The liberated retinol acts as precursor for re-esterification for storage (Blaner et al. 198...