Drug interaction of methadone with oral contraceptive medication. Clinic, treatment and TDM

Introduction:

Drug therapy in patients with methadone and oral contraceptive can be challenging cause of relevant drug interactions which should be taken into account in clinical practice.

Here we present a case of a 22 year old woman. Patient additionally suffered from methadone addiction, affective disorder, attention deficit disorder, Hashimoto-Thyreoiditis and was treated with methadone, bupropion, doxepine and oral contraceptive steroids ethinyl estradiol.

The metabolism of racemic methadone is stereoselective, CYP2B6 preferentially metabolizes (S)-methadone, CYP2C19 preferentially (R)-methadone, and CYP3A4 has no preference [1]. Methadone's major metabolite, 2-ethylidene-1,5-dimethyl- 3,3-diphenylpyrrolidine, does not exhibit pharmacologic activity. At 10 mg/mL of methadone, CYP2C9 and CYP2D6 also generate 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in vitro but in at least 10-fold lower quantities than CYP2B6 [1 – 4]. These CYP enzymes have large interindividual variability and the potential for interactions with inducers and/or inhibitors is well known [5].

Methods:

Clinical course documentation, measurement of drug levels.

Results:

Methadone is in high range before taking ethinyl estradiol (in serum 653 ng/ml, therapeutic range 50 – 400 ng/ml). Methadone serum-level decreased after two month during ethyl estradiol intake (154 ng/ml, 75 ng/ml). After stop oral contraceptives serum level of methadone increase due to 373 ng/ml. Due to the insufficient low methadone serum level, patient suffered from withdrawal symptoms like mydriasis, drug dreams and depressive mood.

Due to the withdrawals of methadone a combination of doxepine and bupropion was chosen, both reached a sufficient plasma level.

Conclusion:

Methadone serum-level decreased during ethinyl estradiol intake and increased after stop taken pills. The treatment of methadone addiction and oral contraceptives indicates the necessity of individualized treatment, taking account therapeutic drug monitoring (TDM) before through and after contraceptives therapy.

References:

[1] Gerber JG, Rhodes RJ, Gal J. Stereoselective metabolism of methadone N-demethylation by cytochrome P4502B6 and 2C19. Chirality. 2004;16: 36 – 44.

[2] Sullivan HR, Due SL. Urinary metabolites of dl-methadone in maintenance subjects. J Med Chem. 1973;16:909 – 913.

[3] Eap CB, Broly F, Mino A, et al. Cytochrome P450 2D6 genotype and methadone steady-state concentrations. J Clin Psychopharmacol. 2001; 21:229 – 234.

[4] Crettol S, Deglon JJ, Besson J, et al. Methadone enantiomer plasma levels, CYP2B6, CYP2C19, and CYP2C9 genotypes, and response to treatment. Clin Pharmacol Ther. 2005;78:593 – 604.

[5] Bomsien S, Skopp G. An in vitro approach to potential methadone metabolic-inhibition interactions. Eur J Clin Pharmacol. 2007;63: 821 – 827.

 

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