P-glycoprotein: Why this drug transporter may be clinically important
If, on the other hand, drug A induces an efflux protein, then drug B would be “kicked out” at a greater rate than normal because the efflux system would be working in overdrive. In this case, tissue concentrations of drug B would be lower than expected and could lead to therapeutic failure. Typically, pharmaceutical companies either do not conduct these induction studies, or if they are performed, they often are not described in prescribing information. This lack of efficacy has been well documented with chemotherapeutic failure caused by drug efflux by BCRP.7 It is likely that Mr. B’s viral load increased when venlafaxine was added to his regimen—the antidepressant induced P-glycoprotein, which reduced indinavir concentrations and subsequent therapeutic effect.
Clinicians should review specific medications they are considering using if the drugs have a narrow therapeutic index or if therapeutic failure from subtherapeutic or supratherapeutic doses would be considered problematic Table.8 Kim9 provides a comprehensive list of P-glycoprotein substrates, inhibitors, and inducers. However, keep in mind that the list of substrates, inhibitors, and inducers changes regularly as new research becomes available.
Table
Selected psychotropics that affect P-glycoprotein
| Substrates | |
| Amitriptyline | Paroxetine |
| Carbamazepine | Quetiapine |
| Chlorpromazine | Risperidone |
| Citalopram | Sertraline |
| Doxepin | Topiramate |
| Nortriptyline | Venlafaxine |
| Olanzapine | |
| Inhibitors | |
| Amitriptyline | Imipramine |
| Carbamazepine | Nefazodone |
| Chlorpromazine | Paroxetine |
| Desipramine | Sertraline |
| Disulfiram | Thioridazine |
| Fluoxetine | Trifluoperazine |
| Fluvoxamine | Trimipramine |
| Haloperidol | |
| Inducersa | |
| Amitriptyline | Phenothiazines |
| Nefazodone | Trazodone |
| aData supporting induction is limited Source: Reference 8 | |
- Linnet K, Ejsing TB. A review on the impact of P-glycoprotein on the penetration of drugs into the brain. Focus on psychotropic drugs. Eur Neuropsychopharmacol. 2008;18(3):157-169.
- Weiss J, Dormann SM, Martin-Facklam M, et al. Inhibition of P-glycoprotein by newer antidepressants. J Pharmacol Exp Ther. 2003;305(1):197-204.
Drug Brand Names
- Amitriptyline • Elavil
- Carbamazepine • Tegretol
- Chlorpromazine • Thorazine
- Citalopram • Celexa
- Desipramine • Norpramin
- Desvenlafaxine • Pristiq
- Disulfiram • Antabuse
- Doxepin • Adapin, Silenor
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Haloperidol • Haldol
- Imipramine • Tofranil
- Indinavir • Crixivan
- Lamivudine and zidovudine • Combivir
- Nefazodone • Serzone
- Nortriptyline • Aventyl, Pamelor
- Olanzapine • Zyprexa
- Paroxetine • Paxil
- Quetiapine • Seroquel
- Risperidone • Risperdal
- Sertraline • Zoloft
- Thioridazine • Melleril
- Topiramate • Topamax
- Trazodone • Desyrel, Oleptro
- Trifluoperazine • Stelazine
- Trimipramine • Surmontil
- Venlafaxine • Effexor
Disclosure
Dr. Levin receives grant/research support from Pfizer.
