5 Course of tranylcypromine enantiomer plasma concentrations in patients with depression

Introduction Tranylcypromine (TCP) is an irreversible monoamine oxidase (MAO)-A/B inhibitor prescribed in treatment resistant depression. Plasma concentrations of TCP enantiomers have not been reported for continuous treatment with the racemic antidepressant to date.

Methods Enantiomer TCP plasma concentrations were measured by a validated liquid-liquid extraction method (LC/MS) after a first single dose and during continuous treatment.

Results Lower plasma concentrations of (+)- TCP than (-)- TCP were found after the first dose of 10 mg TCP with an enantiomer AUC-ratio^(+/-) = 0.04 to 0.16 (n = 3). The AUC-ratio^(+/-) increased to 0.64 for a dose of 20 mg (n = 1), and to 0.88 to 0.94 (n = 4) for 40 mg during continuous treatment of 40 mg/day. Racemic C_Max and AUC were disproportionately high for continuous treatment compared to first single dose.

Conclusions TCP is a special antidepressant drug in that MAO is simultaneously the enantiomer selective pharmacological target and drug metabolizing enzyme. With intact MAO for the first single dose, (+)- TCP is more rapidly metabolized because this enantiomer is a better MAO “suicide” inhibitor than (+)- TCP (ΔLogIC₅₀ > 1). The difference in metabolization vanishes as MAO activity is decreased during continuous treatment. The TCP enantiomer AUC-ratio^(+/-) is therefore a test for peripheral MAO activity and may be a surrogate of central MAO activity. More studies are needed for this interesting pharmacokinetic-pharmacodynamic relationship. For example, recovery of peripheral MAO may be investigated with TCP test doses after discontinuation of TCP, or fluctuations of MAO activity may be detected during long-term treatment.

Publication History

Article published online:
30 April 2020