Effect of interferon alpha-ribavirin bitherapy on cytochrome P450 1A2 and 2D6 and N-acetyltransferase-2 activities in patients with chronic active hepatitis C.
BACKGROUND
Interferon alpha (IFN-alpha) is thought to be responsible for cytochrome P450 (CYP)-dependent drug interactions mediated by a decrease in CYP activities.


OBJECTIVE
The objectives are to determine whether IFN-alpha and ribavirin can alter pretreatment CYP1A2, CYP2D6, CYP3A4 and N-acetyltransferase-2 activities after 1 month of treatment.


METHODS
Enzymatic activities were determined among 14 patients with chronic active hepatitis C before IFN-alpha (3. 10(6) U, 3 times a week) and ribavirin introduction and after 1 month of treatment. During both study periods, subjects received 80 mg dextromethorphan and 140 mg caffeine (1,3,7-trimethylxanthine [137X]). CYP3A4, CYP2D6, and NAT2 activities were assessed by use of urinary metabolic ratios of 3-methoxymorphinan/dextromethorphan, dextrorphan/dextromethorphan, and 5-acetylamino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine(1X). The plasma paraxanthine/caffeine ratio was used to measure CYP1A2 activity.


RESULTS
CYP3A4 and CYP2D6 activities tended to increase after 1 month of antiviral therapy, but the change did not reach statistical significance. CYP1A2 and NAT2 activities were not significantly modified after 1 month of antiviral treatment. Pretreatment activities were significantly lower than those previously observed in healthy volunteers for CYP2D6 (mean +/- SD, 148 +/- 139 versus 759 +/- 692; P =.0008) and CYP3A4 (0.18 +/- 0.06 versus 0.52 +/- 0.72; P =.0006). This difference was no longer statistically significant after 1 month of treatment, because CYP2D6 and CYP3A4 activities improved in 7 patients.


CONCLUSIONS
In patients with chronic hepatitis C, pretreatment CYP3A4 and CYP2D6 activities were significantly lower than those observed in healthy volunteers. These differences disappeared after 1 month of antiviral treatment because of the restoration of these CYP activities in about half of the patients.
Becquemont
Laurent
L
Department of Pharmacology and the Clinical Investigation Center, Saint-Antoine University Hospital, Paris, France. laurent.becquemont@chusa.jussieu.fr
Chazouilleres
Olivier
O
Serfaty
Lawrence
L
Poirier
Jean Marie
JM
Broly
Franck
F
Jaillon
Patrice
P
Poupon
Raoul
R
Funck-Brentano
Christian
C
D000208:Acute Disease; D000217:Acyltransferases / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000963:Antimetabolites / Q000494:pharmacology* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D000963:Antimetabolites; D000998:Antiviral Agents; D016898:Interferon-alpha; D012254:Ribavirin; D019388:Cytochrome P-450 CYP1A2; D019389:Cytochrome P-450 CYP2D6; D000217:Acyltransferases