Is there a risk of pharmacokinetic interaction between desogestrel and propylthiouracil/levothyroxi

Fråga: Is there a risk of pharmacokinetic interaction between desogestrel and propylthiouracil/levothyroxine?

Is there a risk of decreased effect of desogestrel in a patient with thyreotoxicosis?

A patient with thyreotoxicosis has become pregnant despite treatement with desogestrel (Cerazette) taken regularly every day. She was diagnosed with thyreotoxicosis in april 2006, and was treated with propylthiouracil and levothyroxine. Recent laboratory test revealed that she was still hyperthyroid and the dose of propylthiouracil was increased.

Sammanfattning: There is a theoretical possibility that increased levels thyroxine may generally affect drug metabolism. However, since there are no published case reports or other data concerning unwanted pregnancies in patients with desogestrel and hyperthyreosis or on thyroxine treatment, it seems unlikely that such an interaction caused the therapeutic failure in the present case.

Svar: No documentation concerning an interaction between desogestrel and propylthiouracil or levothyroxine has been found in the literature or in medical databases.

From a theoretical point of view, a metabolic interaction between desogestrel and thyroxine can occur. Desogestrel is a prodrug, and bioactivation to 3-keto-desogestrel is needed for contraceptive activity. In vitro studies have implicated CYP2C9 and possibly 2C19 as mediators of bioactivation. 3-keto-desogestrel is then further metabolized by CYP3A4 (1). It is possible that increased levels of thyroxine, may effect CYP3A4 expression and activity (2).

It is well known that patients with hyper-or hypothyroidism may have altered sensitivity to drugs. The metabolism of antipyrine, an NSAID, is increased in patients with hyperthyreosis. The half-life of antipyrine is reduced by approximately 40 %, an effect that is reversed upon normalization of thyroid hormones (2). Thyreotoxicosis has also been associated with an increase in 2-hydroxylation of estrone and estradiol, a process involving CYP3A4 with minor contribution from CYP1A (2,3). However, in an in vitro study of human hepatocytes, thyroxine decreased the protein expression and activity of CYP3A4, while the glucocorticoid dexamethasone and growth hormone had the opposite effect (4).

There is in vitro data showing upregulation of P-Glycoprotein (PgP) by thyroxine and the same effect has been shown in vivo in duodenal specimens from thyroxine treated healthy volunteers (5). It is not known whether desogestrel is a PgP substrate, but it has been demonstrated having an inhibitory effect on PgP (6). Thus, it is difficult to predict the net effect on PgP during concomitant desogestrel and thyroxine treatment.

No information concerning an effect of propylthiouracil on CYP3A4 could be found in the literature.

There are no published case reports or other data concerning unwanted pregnancies in patients with desogestrel and hyperthyreosis or on thyroxine treatment, and therefore it seems unlikely that such an interaction caused the therapeutic failure in the present case. Korhonen T, Tolonen A, Uusitalo J, Lundgren S, Jalonen J, Laine K. The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel. Br J Clin Pharmacol. 2003;60(1):69-75 Farrel G. Effects of disease on expression and regulation of CYPs. Mol Aspects Med. 1999;20(1-2):55-70. Ed Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman´s The pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill; 2006 Liddle C, Goodwin BJ, George J, Tapner M, Farrell GC. Separate and interactive regulation of cytochrome p450 3A4 by triiodothyronine, dexamethasone and growth hormone in cultured hepatocytes. J Clin Endocrinol Metab 1998;83(7):2411-6 Mitin T, von Moltke LL, Court MH, Greenblatt DJ. Levothyroxinee up-regulates P-glycoprotein independent of the pregnane X receptor. Drug Metabol Dispos. 2004;32(8):779-82 Frölich M, Albermann N, Sauer A, Walter-Sack I, Haefeli WE, Weiss J. In vitro and ex vivo evidence for modulation of P-glyckoprotein activity by progestins. Biochemic Pharmacol 2004;68:2409-2416.