Could pyridostigmine (Mestinon) cause lower plasma concentrations of tacrolimus?/nA woman has been

Fråga: Could pyridostigmine (Mestinon) cause lower plasma concentrations of tacrolimus?

A woman has been medicating with pyridostigmine for several years, for myasthenia gravis. She has now received a liver transplant and requires an unexpectedly high tacrolimus dose (40 mg/d) to achieve therapeutic plasma levels of the drug.

Sammanfattning: In vitro data suggests that pyridostigmine may induce CYP3A4, an enzyme mediating tacrolimus metabolism. However, CYP3A4 metabolises a large number of drugs and since there are no reports of pyridostigmine inducing the metabolism of any other drug, the clinical significance of this finding is disputable.

Svar: No reports of a pharmacological interaction between pyridostigmine and tacrolimus were identified in Drugline, Medline or standard pharmacological literature. A textbook on drug interactions mentions only ten known interactions between pyridostigmine and different drug classes, and in none of these pyridostigmine altered the pharmacokinetics of the interacting drug (1).

However, there is one report of pyridostigmine inducing the metabolism of testosterone in vitro (2). When incubated with pyridostigmine, cultivated insect cells expressing human cytochrome P450 3A4 (CYP3A4) converted testosterone into hydroxylated metabolites at an increased rate, indicating a possible induction of CYP3A4. Interestingly, CYP3A4 is the major enzyme in tacrolimus metabolism (3). Stockley IH. Drug interactions. 6th ed. London: The Pharmaceutical Press; 2002 Usmani KA, Rose RL, Hodgson E. Inhibition and activation of the human liver mirosomal and human cytochrome P450 3A4 metabolism of testosterone by deployment-related chemicals. Drug Metab Dispos 2003;31:384-91. Tacrolimus (Prograf). Summary of product characteristics (SPC) (Fujisawa)