© 1992 Oxford University Press
research-article |
Quantitative Plasma Disposition of Retinol and Retinyl Esters after High-Dose Oral Vitamin A Administration in the Cynomolgus Monkey
*Institut für Toxikologie und Embryonalpharmakoiogie, Frece Universität 1000 Berlin 33, Germany
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research Jefferson, Arkansas 72079
Received August 22, 1991; accepted January 17, 1992
A solid-phase extraction technique followed by automated high-performance liquid chromatography sample elution was successfully used to evaluate the effect of three pharmaceutical parameters on the plasma profile of various forms of vitamin A after an oral dose to cynomolgus monkeys. The three parameters evaluated were the chemical form of vitamin A (retinol versus retinyl acetate), the vehicle (acetone/Tween 20/water versus acetone/soybean oil), and the retinol dose (2, 10, and 50 x 103 retinol equivalents/kg). The form of the administered compound, retinol or retinyl acetate, appeared to have no major effect on the formation of nonpolar retinoids. The ester profile in plasma differed depending on whether the dose was administered in the water-based or the oil-based vehicle. Irrespective of the vehicle type the predominant retinoid formed was retinyl palmitate/ oleate. However, retinol doses in the water-based vehicle formed relatively high concentrations of retinyl laurate and retinyl my-ristate but no retinyl linolenate. The retinol dose in the oil-based vehicle formed consistent, but relatively minor, concentrations of retinyl linolenate, higher relative concentrations of retinyl linoleate, and no retinyl laurate or myristate. The dose of retinol administered had an impact on the diversity of the nonpolar retinoid profile. The low dose led to the presence of almost exclusively retinyl palmitate/oleate and retinyl stearate, whereas at higher doses the other retinyl esters became major retinol constituents. These findings are consistent with the hypothesis that, at low doses, the principle esterification pathway is via lecithin:retinol acyltransferase (LRAT) which produces retinyl palmitate, but at higher doses acyl-CoA:retinol acyltransferase is a prominent esterification enzyme, due to the saturation of the LRAT pathway, producing a more diverse profile of retinyl esters.