Answers to a quiz about (CYP450)

Quiz answers, with comments

    • codeine and paroxetine- safe, but, as with many of these questions, they are designed to provide as much information as possible and make you think. If you wish you can regard some of them as ‘trick’ questions. There is of course an interaction here, because Paroxetine will diminish the analgesic effect of codeine, but this is rather unlikely to be dangerous or cause admission to hospital see (1) and the early reference (2).
    • beta-blockers and fluoxetine: increased effect of beta blockers all of which are mainly substrates of 2D6
    • dothiepin and fluvoxamine: there is a paucity of direct evidence that this combination is definitely problematic, but it is likely that dothiepin’s break down will be inhibited by fluvoxamine and because dothiepin is 10 times more toxic than other TCAs this is predicted, and must be assumed, to cause serious problems, until proved otherwise.
    • venlafaxine + bupropion: bupropion is a significant 2D6 inhibitor (3) and will therefore raise levels of venlafaxine increasing its toxicity, and it is already the most toxic of all the new antidepressants, more toxic than some TCAs.
    • venlafaxine + nortriptyline: safe. But this has been put in to illustrate that one might expect improved therapeutic benefit from this combination, because venlafaxine is relatively weak NRI (4,5), so nortriptyline will probably make it into a true dual action combination.
    • phenelzine + dothiepin: No risk of serotonin toxicity, but phenelzine inhibits 2C19, so interaction via 2C19 probable.
    • Phenytoin and imipramine: interaction probable because of imipramine’s inhibition of 2C19.
    • lansoprazole and fluvoxamine: 2C19 interaction definite, but probably beneficial, especially in Scandinavians in whom approximately 20% are ultrarapid metabolisers of 2C19 substrates (6), like all the ’prazoles.
    • warfarin and fluoxetine: danger from increased effect of warfarin.
    • moclobemide + nortriptyline: Probably safe. There is no risk of serotonin toxicity; and moclobemide, which would upset many drugs, will probably increase nortriptyline, which is pure 2D6 substrate, only moderately. So an increase in side effects is likely, but probably not going to be serious.
    • moclobemide + imipramine: Double trouble, potentially fatal interaction. First moclobemide will impair the breakdown of imipramine, thereby increasing its levels (via its inhibition of 1A2, 2D6 and 2C19). Without this interaction, most of the time, you would probably get away with this combination, despite the risk of serotonin toxicity, because imipramine is a weak SRI.
      However extensive data indicates that high blood levels of imipramine will produce a much greater risk, and therefore the secondary point here is that the risk of serotonin toxicity would be substantially increased. A nice, or rather a nasty, little example of the crucial difference a phamacokinetic contribution can make to a pharmacodynamic interaction.
    • moclobemide + phenytoin: phenytoin levels increased because of moclobemide’s inhibition of 2C19.
    • erythromycin and ergotamine: people have lost limbs because of this interaction, as a result of erythromycin’s inhibition of 3A4.
    • ketoconazole and sildenafil: likewise ketoconazole is a potent 3A4 inhibitor and will increase sildenafil (7).
    • sodium valproate and lorazepam: no P450 interaction, but there do seem to be pronounced interactions between valproate and some benzodiazepines, particularly lorazepam in my experience, which produces a greatly increased sedative effect. Some caution and moderation of dosage may be appropriate.
    • fluvoxamine + imipramine: raised levels of imipramine, quite probably to a degree that will be dangerous. A similar interaction with clomipramine can raise levels to over 1200 mg/l (8).
    • fluvoxamine + nortriptyline: safe, but not recommended, because the only CYP450 isoform fluvoxamine does not inhibit is 2D6.
    • fluvoxamine + caffeine: definite increase in risk of adverse and possibly toxic effects from caffeine, because of fluvoxamine’s extraordinarily potent inhibition of CYP450 1A2. This may include cardiac problems, and even possibly increased rates of spontaneous abortion (9-11).
    • clozapine + fluoxetine: Serious multiple interaction raising clozapine levels with the attendant increased risk for all clozapine side effects and toxic effects, particularly cardiac and epileptogenic effects.
    • thioridazine + fluvoxamine: same as above
    • clozapine + mirtazapine: No P450 interaction. However this would be a particularly ill-advised combination because both these drugs are potently sedative via inhibition of histamine H1 receptors.
    • risperidone + benztropine: No clearly documented P450 interaction, however case reports strongly suggest that benztropine is a 2D6 inhibitor, as is Risperidone (12,13). So they will bloch each others breakdown. Increased risperidone side effects predicted and possible delirium from anti-muscarinic effects of benztropine. I am aware of cases where this has led to disastrous scenarios. Delirium misinterpreted as a worsening of so psychosis, leading to increased doses, toxicity, intensive care admission, and frightening complications.
      Unfortunately, because this combination does not produce obvious problems very frequently, many people may think it is innocuous. If you audited the clinical course of 100 patients on this combination you would find the complications predicted above much more frequently than with similar combinations that are devoid of those CYP450 interactions.
    • risperidone + citalopram: same as above, citalopram and Escitalopram are both significant 2D6 inhibitors. Also note, the evidence relating to risperidone’s extrapyramidal side-effects has been questioned in a most serious way, with strong suggestions of irregularities in data collection and handling by the pharmaceutical company (14).
    • risperidone + sertraline: Safe, no significant P450 interaction.
    • bupropion + tranylcypromine: Appears to be safe. Bupropion is a 2D6 inhibitor but not apparently a significant reuptake inhibitor, certainly not of serotonin. If it were a significant dopamine reuptake inhibitor it might cause amphetamine like toxicity mixed with tranylcypromine. This appears not to occur. This combination has been used safely, and there appear to be no reports in the literature of toxicity with this combination.
    • bupropion + clozapine: More double trouble. Both are 2D6 inhibitors and rapid transition to toxic levels because of non-linear phamacokinetics may be expected. Also, both these drugs are amongst the most potently epileptogenic of all psychotropics, that is why bupropion was taken off the market back in the 1980s.
    • bupropion + chlorpheniramine: Same again, both 2D6 inhibitors.
    • fluoxetine + pimozide: Although it looks like pimozide is being widely withdrawn the principle is similar for many neuroleptics. Fluoxetine interfears with most of them, and many of them have significant toxicity. In this case cardiac via prolongation of Qtc. But remember that applies, to a greater or lesser extent, with most of the antidepressants and neuroleptics.
    • fluoxetine + moclobemide: double trouble again. Major P450 interaction both ways with expected substantial elevations of blood levels of both drugs, thereby much increasing the likelihood of a life threatening serotonin toxicity reaction. One off the most ill-advised combinations of this sort that one can imagine, but somebody has tried it.
    • fluoxetine + reboxetine: no major problem anticipated, but some elevation of reboxetine possible. Possible increased therapeutic benefit through generation of dual-action effect; but not a recommended way to achieve that.

References

1. Tirkkonen, T and Laine, K, Drug interactions with the potential to prevent prodrug activation as a common source of irrational prescribing in hospital inpatients. Clin Pharmacol Ther, 2004. 76(6): p. 639-47.

2. Dayer, P, Desmeules, J, and Striberni, R, In vitro forecasting of drugs that may interfere with codeine bioactivation. Eur J Drug Metab Pharmacokinet, 1992. 17(2): p. 115-20.

3. Kennedy, SH, et al., Combining bupropion SR with venlafaxine, paroxetine, or fluoxetine: a preliminary report on pharmacokinetic, therapeutic, and sexual dysfunction effects. J Clin Psychiatry, 2002. 63(3): p. 181-6.

4. Debonnel, G, et al., Differential physiological effects of a low dose and high doses of venlafaxine in major depression. International Journal of Neuropsychopharmacology, 2006: p. 1-11.

5. Blier, P, et al., Effects of different doses of venlafaxine on serotonin and norepinephrine reuptake in healthy volunteers. International Journal of Neuropsychopharmacology, 2006: p. 1-10.

6. Sim, SC, et al., A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clinical Pharmacology and Therapeutics, 2006. 79(1): p. 103-13.

7. Hyland, R, et al., Identification of the cytochrome P450 enzymes involved in the N-demethylation of sildenafil. Br J Clin Pharmacol, 2001. 51(3): p. 239-48.

8. Szegedi, A, et al., Combination treatment with clomipramine and fluvoxamine: drug monitoring, safety, and tolerability data. Journal of Clinical Psychiatry, 1996. 57(6): p. 257-64.

9. Higdon, JV and Frei, B, Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr, 2006. 46(2): p. 101-23.

10. Signorello, LB, et al., Caffeine metabolism and the risk of spontaneous abortion of normal karyotype fetuses. Obstet Gynecol, 2001. 98(6): p. 1059-66.

11. Cornelis, MC, et al., Coffee, CYP1A2 genotype, and risk of myocardial infarction. Jama, 2006. 295(10): p. 1135-41.

12. Armstrong, SC and Schweitzer, SM, Delirium associated with paroxetine and benztropine combination. Am J Psychiatry, 1997. 154(4): p. 581-2.

13. Byerly, MJ, Christensen, RC, and Evans, OL, Delirium associated with a combination of sertraline, haloperidol, and benztropine. Am J Psychiatry, 1996. 153(7): p. 965-6.

14. Huston, P and Moher, D, Redundancy, disaggregation, and the integrity of medical research. Lancet, 1996. 347(9007): p. 1024-6.