Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone

David J. Greenblatt, Lisa L. Von Moltke, Jerold S. Harmatz, Steven M. Fogelman, Gengsheng Chen, Jennifer A. Graf, Polyxane Mertzanis, Susan Byron, Kerry E. Culm, Brian W. Granda, Johanna P. Daily, Richard I. Shader

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Antiretroviral agents may participate in drug interactions that influence the efficacy and toxicity of other antiretrovirals, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor, ritonovir, may cause drug interactions by inhibiting the activity of cytochrome P450-3A (CYP3A) isoforms. In a single-dose, blinded, four-way crossover study, 10 healthy volunteer subjects received 50 mg of trazodone hydrochloride or matching placebo concurrent with low-dose ritonavir (four doses of 200 mg each) or with placebo. Compared to the control condition, ritonovir significantly reduced apparent oral clearance of trazodone (155 ± 23 vs. 75 ± 12 ml/min, p < 0.001), prolonged elimination half-life (6.7 ± 0.7 vs. 14.9 ± 3.9 h, p < 0.05), and increased peak plasma concentrations (842 ± 64 vs. 1125 ± 111 ng/ml, p < 0.05) (mean ± SE). Coadministration of trazodone with ritonavir increased sedation, fatigue, and performance impairment compared to trazodone plus placebo; differences reached significance only for the digit-symbol substitution test. Three subjects experienced nausea, dizziness, or hypotension when trazodone was given with ritonavir; 1 of these subjects also experienced syncope. Thus short-term low-dose administration of ritonavir impairs oral clearance of trazodone and increases the occurrence of adverse reactions. The findings are consistent with impairment of CYP3A-mediated trazodone metabolism by ritonovir.

Original languageEnglish (US)
Pages (from-to)414-422
Number of pages9
JournalJournal of Clinical Pharmacology
Volume43
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Fingerprint

Trazodone
Ritonavir
Cytochrome P-450 CYP3A
Placebos
Drug Interactions
Healthy Volunteers
Anti-Retroviral Agents
Syncope
Dizziness
Protease Inhibitors
Hypotension
Cross-Over Studies
Nausea
Fatigue
Half-Life
Protein Isoforms

Keywords

  • Cytochrome P450-3A
  • Drug interactions
  • Ritonavir
  • Trazodone
  • Viral protease inhibitors

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

Greenblatt, D. J., Von Moltke, L. L., Harmatz, J. S., Fogelman, S. M., Chen, G., Graf, J. A., ... Shader, R. I. (2003). Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone. Journal of Clinical Pharmacology, 43(4), 414-422. https://doi.org/10.1177/0091270003251864

Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone. / Greenblatt, David J.; Von Moltke, Lisa L.; Harmatz, Jerold S.; Fogelman, Steven M.; Chen, Gengsheng; Graf, Jennifer A.; Mertzanis, Polyxane; Byron, Susan; Culm, Kerry E.; Granda, Brian W.; Daily, Johanna P.; Shader, Richard I.

In: Journal of Clinical Pharmacology, Vol. 43, No. 4, 01.04.2003, p. 414-422.

Research output: Contribution to journalArticle

Greenblatt, DJ, Von Moltke, LL, Harmatz, JS, Fogelman, SM, Chen, G, Graf, JA, Mertzanis, P, Byron, S, Culm, KE, Granda, BW, Daily, JP & Shader, RI 2003, 'Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone', Journal of Clinical Pharmacology, vol. 43, no. 4, pp. 414-422. https://doi.org/10.1177/0091270003251864
Greenblatt, David J. ; Von Moltke, Lisa L. ; Harmatz, Jerold S. ; Fogelman, Steven M. ; Chen, Gengsheng ; Graf, Jennifer A. ; Mertzanis, Polyxane ; Byron, Susan ; Culm, Kerry E. ; Granda, Brian W. ; Daily, Johanna P. ; Shader, Richard I. / Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone. In: Journal of Clinical Pharmacology. 2003 ; Vol. 43, No. 4. pp. 414-422.
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