A comparative study on the effects of oral amiodarone and trimeprazine, twoin vitroretinyl ester hydrolase inhibitors, on the metabolic availability of vitamin A in rats

Abstract

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...

Drop‐to‐drop solvent microextraction coupled with gas chromatography/mass spectrometry for rapid determination of trimeprazine in urine and blood of rats: application to pharmacokinetic studies

“…Trimeprazine tartrate is also useful in the short‐term treatment for night waking in young children. However, high doses of this drug may cause side effects such as photosensitive dermatitis, drowsiness, abdominal discomfort and reduction in the level of serum thyroid hormones 1–3. Various methods have been applied for the separation and determination of trimeprazine in different matrices including high‐performance liquid chromatography (HPLC),4, 5 capillary electrophoresis (CE),6 flow injection analysis (FIA),7, 8 ultraviolet‐visible (UV‐VIS) spectrophotometry,9 liquid chromatography/mass spectrometry (LC/MS),10 and gas chromatography/mass spectrometry (GC/MS) 11.…”