Double Issue
Bupropion is commonly added to other antidepressants because of its sexual-saving effects. Bruce Gaulin has brought to my attention that there is evidence that it is a CYP2D6 inhibitor and can raise the maximal concentration of desipramine 2-fold in unpublished studies cited in its drug insert. This is supported by a case report of elevated imipramine levels when BUP was added (Shad 1997). It is possible that all antidepressants that are CYP2D6 substrates will be vulnerable, but antidepressants that have CYP2D6 as a single substrate pathway will be mostvulnerable (e.g., desipramine and paroxetine). However, there is another possibility that would explain the same data-- i.e., that DMI and IMI are substrates of CYP2B6 since it is known that bupropion is both a substrate and an inhibitor of this CYP.
A new study shows that since bupropion is a substrate of CYP2B6 it concentration will be increased by anti-depressants thatare inhibitors of CYP2B6 (e.g., paroxetine , fluvoxamine, sertraline, and fluoxetine, Hesse et al 2000). Clinicians should be aware of these possible interactions in their prescribing.
Hesse LM, et al: CYP2B6 mediates the in vitro hydroxylation of bupropion: potential drug interactions with other antidepressants.Drug Metab Dispos. 2000 Oct;28(10):1176-83.
Shad MU, Preskorn SH.: A possible bupropion and imipramine interaction. J Clin Psychopharmacol. 1997 17:118-9.
Propoxyphene (Darvon) is an analgesic that has been available for many years. It is a racemic compound, and its D-enantiomer is the active form. Darvon is metabolized by an unknown CYP via N-demethylation to norpropoxyphene which is also active (may be CYP 1 A2 since Darvon is known to be induced by smoking, Boston Coll Study 1981). Although the CYPs involved in Darvon's metabolism have not been clarified, Darvon is known to be an inhibitor of at least 3 CYPs: 2C9, 2D6 and 3A. The only Ki that is known is for CYP2D6 of 6.
Despite the fact that Darvon has been around a long time, only a few drug interactions are well established. Darvon has been extensively described (10-15 case reports and clinical studies) to significantly increase concentration of CBZ (60%, presumably by blocking CYP 3A since it decreases the epoxide Bergendal 1997). With co-administration, Darvon significantly increases the concentration of alprazolam (presumably by the same CYP3A inhibition, Abernethy 1985). Since Darvon can inhibit these CYP3A substrates, it is possible that it can affect others as well although the data is not available.
Darvon has the potential to be a significant inhibitor of CYP2D6, and it increases concentration of doxepin which is a substrate of CYP 2D6 (Abernethy 1982) and metoprolol and increases concentration of orphenadrine variably (Product insert). Darvon increases the concentration of phenobarbital by 20%, although the mechanism is not clear (since phenobarbital's metabolism has not been well defined, Hansen 1980).
Abernethy DR, Greenblatt DJ, Steel K, Shader RI.Impairment of hepatic drug oxidation by propoxyphene.Ann Intern Med. 1982 Aug;97(2):223-4. PMID: 7103282
Abernethy DR, Greenblatt DJ, Morse DS, Shader RI Interaction of propoxyphene with diazepam, alprazolam and lorazepam. Br J Clin Pharmacol 1985 Jan;19(1):51-7 PMID: 2858217
Bergendal L, Friberg A, Schaffrath AM, Holmdahl M, Landahl S. The clinical relevance of the interaction between carbamazepine and dextropropoxyphene in elderly patients in Gothenburg, Sweden. Eur J Clin Pharmacol 1997;53(3-4):203-6 Boston Collaborative Study Clin Pharmacol Ther 1973: 14, 259
Hansen BS, Dam M, Brandt J, Hvidberg EF, Angelo H, Christensen JM, Lous P.Influence of dextropropoxyphene on steady state serum levels and protein binding of three anti-epileptic drugs in man. Acta Neurol Scand. 1980 Jun;61(6):357-67. PMID: 6998251
Lungborg P: The effect of Propoxyphene pretreatment on the disposition of metoprolol and propanolol. Clin Pharmacol Ther 1981: 29: 263