The metabolism and pharmacokinetics of isotretinoin in patients with acne and rosacea are not influenced by ethanol.
BACKGROUND
Isotretinoin is effective in the treatment of severe acne and rosacea. Both parent drug and its main metabolite 4-oxo-isotretinoin are potentially teratogenic compounds and contain a carboxylic acid moiety. In the presence of ethanol, naturally occurring as well as synthetic retinoids also containing a carboxylic acid moiety are capable of undergoing an ethyl esterification with the metabolic formation of more lipophilic compounds with a much longer terminal half-life.


OBJECTIVE
To determine if isotretinoin (13-cis-RA), its main metabolite 4-oxo-isotretinoin (4-oxo-13-cis-RA), and other possible metabolites in the presence or absence of ethanol are converted to their corresponding ethyl derivatives in patients with severe acne or rosacea after multiple isotretinoin dosing. In addition, pharmacokinetic parameters of the parent drug and its 4-oxo metabolite were determined.


METHODS
Eleven patients with severe acne or rosacea were treated with isotretinoin daily for 3 months and investigated pharmacokinetically during 24 h after 1 month of treatment and for up to 28 days after discontinuation of therapy. A possible influence of ethanol was evaluated using a simple self-administered questionnaire and by measuring serum ethanol levels during treatment. The concentrations of isotretinoin, 4-oxo-isotretinoin and possible ethylated and nonethylated metabolites were measured by reverse-phase high-performance liquid chromatography.


RESULTS
Although seven of 11 patients had a considerable weekly alcohol intake, no endogenous synthesis of ethyl derivatives of isotretinoin, the main 4-oxo metabolite or the all-trans compounds was chromatographically detectable in any of the patients' plasma samples during the treatment period. Multiple dose pharmacokinetic data for the parent drug and its main metabolite were comparable to previous studies.


CONCLUSIONS
The metabolism and pharmacokinetics of isotretinoin and its main metabolites are not influenced by ethanol during long-term isotretinoin treatment. After ceasing long-term isotretinoin therapy the recommended period of 1 month for using anticonceptive measures in fertile women seems adequate.
Grønhøj Larsen
F
F
Department of Dermatology, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark. fregro01@geh.regionh.dk
Jakobsen
P
P
Grønhøj Larsen
C
C
Heidenheim
M
M
Held
E
E
Nielsen-Kudsk
F
F
D000152:Acne Vulgaris / Q000097:blood* / Q000188:drug therapy; D000328:Adult; D000428:Alcohol Drinking; D002851:Chromatography, High Pressure Liquid; D003879:Dermatologic Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D000431:Ethanol / Q000378:metabolism*; D005260:Female; D006801:Humans; D015474:Isotretinoin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012393:Rosacea / Q000097:blood* / Q000188:drug therapy; D011795:Surveys and Questionnaires; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D055815:Young Adult
D003879:Dermatologic Agents; C002202:4-oxoretinoic acid; D000431:Ethanol; D014212:Tretinoin; D015474:Isotretinoin