Differential impairment of triazolam and zolpidem clearance by ritonavir

David J. Greenblatt, Lisa L. Von Moltke, Jerold S. Harmatz, Anna Liza B Durol, Johanna P. Daily, Jennifer A. Graf, Polyxane Mertzanis, Jonathan L. Hoffman, Richard I. Shader

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

Background: The viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450-3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases. Methods: The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (four doses of 200 mg), or with placebo. Results: Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to <4% of control values (p < .005), prolonged elimination half-life (41 versus 3 hours; p < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p < .08), and slightly prolonged elimination half-life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir. Conclusion: Short-term low-dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A.

Original languageEnglish (US)
Pages (from-to)129-136
Number of pages8
JournalJournal of Acquired Immune Deficiency Syndromes
Volume24
Issue number2
StatePublished - Jun 1 2000
Externally publishedYes

Fingerprint

Triazolam
Ritonavir
Cytochrome P-450 CYP3A
Hydroxylation
Benzodiazepines
Half-Life
zolpidem
Liver Microsomes
Biotransformation
Protease Inhibitors
Hypnotics and Sedatives
Drug Interactions
Double-Blind Method
Volunteers
Protein Isoforms
Placebos

Keywords

  • Cytochrome P450-3A
  • Drug interactions
  • In vitro metabolism
  • Ritonavir
  • Triazolam
  • Viral protease inhibitors
  • Zolpidem

ASJC Scopus subject areas

  • Virology
  • Immunology

Cite this

Greenblatt, D. J., Von Moltke, L. L., Harmatz, J. S., Durol, A. L. B., Daily, J. P., Graf, J. A., ... Shader, R. I. (2000). Differential impairment of triazolam and zolpidem clearance by ritonavir. Journal of Acquired Immune Deficiency Syndromes, 24(2), 129-136.

Differential impairment of triazolam and zolpidem clearance by ritonavir. / Greenblatt, David J.; Von Moltke, Lisa L.; Harmatz, Jerold S.; Durol, Anna Liza B; Daily, Johanna P.; Graf, Jennifer A.; Mertzanis, Polyxane; Hoffman, Jonathan L.; Shader, Richard I.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 24, No. 2, 01.06.2000, p. 129-136.

Research output: Contribution to journalArticle

Greenblatt, DJ, Von Moltke, LL, Harmatz, JS, Durol, ALB, Daily, JP, Graf, JA, Mertzanis, P, Hoffman, JL & Shader, RI 2000, 'Differential impairment of triazolam and zolpidem clearance by ritonavir', Journal of Acquired Immune Deficiency Syndromes, vol. 24, no. 2, pp. 129-136.
Greenblatt DJ, Von Moltke LL, Harmatz JS, Durol ALB, Daily JP, Graf JA et al. Differential impairment of triazolam and zolpidem clearance by ritonavir. Journal of Acquired Immune Deficiency Syndromes. 2000 Jun 1;24(2):129-136.
Greenblatt, David J. ; Von Moltke, Lisa L. ; Harmatz, Jerold S. ; Durol, Anna Liza B ; Daily, Johanna P. ; Graf, Jennifer A. ; Mertzanis, Polyxane ; Hoffman, Jonathan L. ; Shader, Richard I. / Differential impairment of triazolam and zolpidem clearance by ritonavir. In: Journal of Acquired Immune Deficiency Syndromes. 2000 ; Vol. 24, No. 2. pp. 129-136.
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abstract = "Background: The viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450-3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases. Methods: The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (four doses of 200 mg), or with placebo. Results: Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to <4{\%} of control values (p < .005), prolonged elimination half-life (41 versus 3 hours; p < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78{\%} of control values (p < .08), and slightly prolonged elimination half-life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir. Conclusion: Short-term low-dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A.",
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AU - Daily, Johanna P.

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