title: Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study.
abstract: BACKGROUND
  Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes. There have been no previous studies designed to investigate a potential pharmacokinetic (PK) interaction between MCB and VPA or CBZ; however, these agents are likely to be used concomitantly for the treatment of depressive disorders.
  
  
  CONCLUSIONS
  VPA does not significantly affect PK or metabolism of MCB at steady state. CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration.
  
  
  OBJECTIVE
  To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients.
  
  
  METHODS
  Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales.
  
  
  RESULTS
  CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l(-1); 95% confidence interval (CI) -4.84863, -0.66194; P = 0.01] and C(max) by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h(-1) kg(-1); 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l(-1); 95% CI -0.77479, -0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior to the controls, for several possible reasons. Overall tolerability of all study medications was good.
  
  
  CONCLUSIONS
  VPA does not significantly affect PK or metabolism of MCB, whereas CBZ time-dependently decreases MCB exposure, probably by inducing metabolism of MCB and its major plasma metabolite. The actual clinical relevance of the observed MCB-CBZ PK interaction needs to be further evaluated in a more comprehensive study.
authors.affiliation: Medicines and Medical Devices Agency of Serbia, Vojvode Stepe No. 458, Belgrade, Serbia. anitarakic@beotel.yu
authors.forename: Anita
authors.initials: A
authors.lastname: Rakic Ignjatovic
authors.forename: Branislava
authors.initials: B
authors.lastname: Miljkovic
authors.forename: Dejan
authors.initials: D
authors.lastname: Todorovic
authors.forename: Ivana
authors.initials: I
authors.lastname: Timotijevic
authors.forename: Milena
authors.initials: M
authors.lastname: Pokrajac
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000928:Antidepressive Agents / Q000627:therapeutic use*; D018692:Antimanic Agents / Q000627:therapeutic use*; D002220:Carbamazepine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016022:Case-Control Studies; D003866:Depressive Disorder / Q000188:drug therapy*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020912:Moclobemide / Q000378:metabolism / Q000493:pharmacokinetics*; D011569:Psychiatric Status Rating Scales; D013997:Time Factors; D016896:Treatment Outcome; D014635:Valproic Acid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D018692:Antimanic Agents; D002220:Carbamazepine; D014635:Valproic Acid; D020912:Moclobemide