Exposure to Retinyl Esters, Retinol, and Retinoic Acids in Non-Pregnant Women following Increasing Single and Repeated Oral Doses of Vitamin A

Vol. 49, No. 3, 2005

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Original Paper

Exposure to Retinyl Esters, Retinol, and Retinoic Acids in Non-Pregnant Women following Increasing Single and Repeated Oral Doses of Vitamin A
Stefan Hartmann^a, Odd Brørs^b, Jürgen Bock^c, Rune Blomhoff^d, Jochen Bausch^a, Ulf-W. Wiegand^c, Dieter Hartmann^c, Dietrich H. Hornig^a

^aRoche Vitamins Ltd, Basel, Switzerland;
^bDepartment of Clinical Chemistry, Ulleval University Hospital, Oslo, Norway;
^cPharmaceutical Division, F. Hoffmann-La Roche Ltd, Basel, Switzerland, and
^dInstitute for Nutrition Research, University of Oslo, Oslo, Norway

Address of Corresponding Author

Ann Nutr Metab 2005;49:155-164 (DOI: 10.1159/000086879)

Key Words

Retinol
Retinyl esters
Retinoic acids
Vitamin A exposure
Vitamin A, non-pregnant females
Vitamin A, single and repeated doses
Safety of vitamin A

Abstract

Background: High intakes of vitamin A cause congenital malformations in experimental animals with elevated generation of retinoic acids (RA). Results in humans are conflicting. Objective: To evaluate plasma concentration-time curves of retinyl esters, retinol and their metabolites at increasing doses of vitamin A. Methods: An open-label dose-response study. Non-pregnant females (3 groups with n = 12; 18-40 years) received once daily oral doses of vitamin A palmitate up to 30,000 IU/day over 21 days. The area under the plasma concentration-time curve (AUC_24h) served as indicator for exposure. Results: AUC_24h of retinyl esters increased linearly with dose. Retinol concentrations were unaffected. All-trans RA exhibited a diurnal-like concentration-time profile (C_maxat 3 h; C_minat 8 h), concentrations decreasing below pre-dose levels at 5 h and regaining pre-dose levels at 16 h. The maximum temporary increase in exposure was 33% (single dose) and 19% (repeated doses) above baseline, but AUC_24h remained unaltered. AUC_24h increased linearly with dose for 13-cis RA and 13-cis-4-oxo RA. Repeated doses caused a 25% increase in exposure with the highest vitamin A intake. Accumulation of 13-cis- 4-oxo RA at 30,000 IU/day doubled compared to the 4,000 IU/day intake. Conclusion: Repeated oral doses of up to 30,000 IU of vitamin A in addition to dietary vitamin A were without safety concern. Safe doses are probably higher, since plasma concentrations and exposure to RA remained at levels earlier shown to be without increased risk of teratogenicity in pregnant women.

Author Contacts

Jochen Bausch
DSM Nutritional Products
PO Box 3255
CH-4002 Basel (Switzerland)
Tel. +41 61 6882844, Fax +41 61 6886819, E-Mail jochen.bausch@dsm.com

Article Information

Received: June 5, 2004
Accepted: December 20, 2004
Published online: July 7, 2005
Number of Print Pages : 10
Number of Figures : 7, Number of Tables : 3, Number of References : 32

Medline Abstract (ID 16006784)

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