Pharmacokinetics of retinoids in women after meal consumption or vitamin A supplementation.
These studies were conducted to evaluate the pharmacokinetics of several retinoids after meal consumption or vitamin A supplementation to establish a reference for future assessment of teratogenic risks of retinoid therapeutic agents. In the first study, 36 healthy young female volunteers consumed single meals containing vitamin A amounts ranging from 1,305 to 169,474 IU. In the second study, 24 other female volunteers took vitamin A supplements at a dose level of 5,000, 10,000, or 25,000 IU/day for 60 days. Plasma concentrations of tretinoin, isotretinoin, 4-oxo-tretinoin, and 4-oxo-isotretinoin in samples collected during the studies were analyzed using a high-performance liquid chromatography method with ultraviolet detection. Pharmacokinetic parameters for the retinoids were calculated using model-independent methods. Plasma concentrations of tretinoin were not altered by meal consumption or vitamin A supplementation. Plasma levels of 4-oxo-tretinoin were below the assay detection limit (0.3 ng/mL) in the majority of samples collected throughout the studies. Linear relationships between dose and maximum concentration (Cmax) and dose and area under the concentration-time curve (AUC) for isotretinoin and 4-oxo-isotretinoin were derived from data from the meal study. For the most bioavailable formulation used in the supplement study, daily ingestion of 5,000 IU of vitamin A caused increases of 141 +/- 53% and 171 +/- 77% from baseline in the 24-hour AUCs of isotretinoin and 4-oxo-isotretinoin, respectively. Dose-related increases in systemic exposure to retinoids were observed after ingestion of vitamin A by means of a meal or a supplement. Findings from these studies can be used as a basis for future safety evaluations of retinoid compounds.
Chen
C
C
Department of Clinical Pharmacology, Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA.
Mistry
G
G
Jensen
B
B
Heizmann
P
P
Timm
U
U
van Brummelen
P
P
Rakhit
A K
AK
D000328:Adult; D019540:Area Under Curve; D004347:Drug Interactions; D005260:Female; D005502:Food; D005504:Food Analysis; D018565:Food-Drug Interactions; D006801:Humans; D015474:Isotretinoin / Q000493:pharmacokinetics; D007641:Keratolytic Agents / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D012176:Retinoids / Q000097:blood / Q000493:pharmacokinetics*; D014212:Tretinoin / Q000493:pharmacokinetics; D014801:Vitamin A / Q000008:administration & dosage* / Q000032:analysis
D007641:Keratolytic Agents; D012176:Retinoids; D014801:Vitamin A; D014212:Tretinoin; D015474:Isotretinoin