Vitamin A Metabolism is Altered in Brown Norway and Long-Evans Rats Infused with Naftidrofuryl or Erythromycin Intravenously

Abstract

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.

Flupenthixol and cefotiam: effects on vitamin A metabolism in rats

“…Changes in hepatic retinyl ester composition require a concerted adaptation of vitamin A metabolism, adjusted by hydrolytic and synthetic activities for esterified retinol. Therefore, this and a previous study (Schindler et al 2002) also sought to determine whether in vivo dosing with REH inhibitors can produce subsequent alterations in liver vitamin A ester profile. The major finding of this and our earlier (Schindler et al 2002) investigation was that treatment of LE rats with naftidrofuryl or erythromycin caused a considerable increase in the relative amount of RP and RO, mainly at the expense of other retinyl esters.…”

“…stearoyl chloride, linoleoyl chloride, myristoyl chloride, oleoyl chloride) were purchased from Sigma (Deisenhofen, Germany). The suppliers of other reagents and chemicals have been reported earlier (Schindler et al 2002). All chemicals and solvents were of analytical grade.…”

“…Therefore, they were calculated and represented as two fractions. Stock solution of retinol (dissolved in light petroleum ether (40 -608C)), RM, RL, RP, RO and RS (each dissolved in ethanol) standards were prepared as described previously (Schindler et al 2002) and verified by the absorbance of a 1 % solution at 325 nm 1830, 990, 900, 940, 890, 870 respectively (Thompson et al 1971;Bhat & Lacroix, 1983). All the HPLC analyses were performed at room temperature (20^28C).…”

“…1. For modelling the covariance structure of the repeated measurement data, we used the SAS procedure MIXED (version 6.12, 1996; SAS Institute Inc., Cary, NC, USA) as described in our previous publication (Schindler et al 2002). A suitable structure type was 'heterogeneous compound symmetry', i.e.…”

“…Rats are the most common laboratory model for investigating vitamin A metabolism. However, inter-strain differences in both vitamin A metabolism and responsiveness to drug administration are known to exist among rats, making extrapolation of data from one strain to another difficult (Pirovino et al 1990;Seifert et al 1991;Lahmame & Armario, 1996;Tuitoek et al 1996;Schindler et al 2002). Therefore, another factor considered when designing the present study was the rat strain.…”