Inhibition of desipramine hydroxylation (cytochrome P450-2D6)in vitro by quinidine and by viral protease inhibitors

Relation to drug interactions in vivo

Lisa L. Von Moltke, David J. Greenblatt, Su Xiang Duan, Johanna P. Daily, Jerold S. Harmatz, Richard I. Shader

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Pharmacokinetic drug interactions with viral protease inhibitors are of potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhibitors with substrates of cytochrome P450-2D6. Biotransformation of desipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhibitors currently used to treat human immunodeficiency virus infection were tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean K(m) value of 11.7 μM (range: 9.9- 15.3 μM). Quinidine, a highly potent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mean inhibition constant of 0.16 μM (range: 0.13-0.18 μM). All four protease inhibitors impaired OH-DMI formation; the pattern was consistent with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were as follows: ritonavir, 4.8 μM; indinavir, 15.6 μM; saquinavir, 24.0 μM; nelfinavir, 51.9 μM. In a clinical pharmacokinetic study, coadministration of ritonavir with DMI inhibited DMI clearance by an average of 59%. The in vitro findings, together with observed plasma ritonavir concentrations, provided a reasonable quantitative forecast of this interaction, whereas estimated unbound plasma or intrahepatic ritonavir concentrations yielded poor quantitative forecasts. Thus the in vitro model correctly identifies ritonavir as a potent and clinically important inhibitor of human P450-2D6. Other protease inhibitors may also inhibit 2D6 activity in humans, but with lower potency than ritonavir.

Original languageEnglish (US)
Pages (from-to)1184-1189
Number of pages6
JournalJournal of Pharmaceutical Sciences
Volume87
Issue number10
DOIs
StatePublished - Oct 1998
Externally publishedYes

Fingerprint

Drug interactions
Cytochrome P-450 CYP2D6
Hydroxylation
Desipramine
Quinidine
Protease Inhibitors
Drug Interactions
Ritonavir
Pharmacokinetics
Human Activities
Nelfinavir
Saquinavir
Indinavir
Plasmas
In Vitro Techniques
Beam plasma interactions
Liver Microsomes
Virus Diseases
Biotransformation
Viruses

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science

Cite this

Inhibition of desipramine hydroxylation (cytochrome P450-2D6)in vitro by quinidine and by viral protease inhibitors : Relation to drug interactions in vivo. / Von Moltke, Lisa L.; Greenblatt, David J.; Duan, Su Xiang; Daily, Johanna P.; Harmatz, Jerold S.; Shader, Richard I.

In: Journal of Pharmaceutical Sciences, Vol. 87, No. 10, 10.1998, p. 1184-1189.

Research output: Contribution to journalArticle

Von Moltke, Lisa L. ; Greenblatt, David J. ; Duan, Su Xiang ; Daily, Johanna P. ; Harmatz, Jerold S. ; Shader, Richard I. / Inhibition of desipramine hydroxylation (cytochrome P450-2D6)in vitro by quinidine and by viral protease inhibitors : Relation to drug interactions in vivo. In: Journal of Pharmaceutical Sciences. 1998 ; Vol. 87, No. 10. pp. 1184-1189.
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abstract = "Pharmacokinetic drug interactions with viral protease inhibitors are of potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhibitors with substrates of cytochrome P450-2D6. Biotransformation of desipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhibitors currently used to treat human immunodeficiency virus infection were tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean K(m) value of 11.7 μM (range: 9.9- 15.3 μM). Quinidine, a highly potent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mean inhibition constant of 0.16 μM (range: 0.13-0.18 μM). All four protease inhibitors impaired OH-DMI formation; the pattern was consistent with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were as follows: ritonavir, 4.8 μM; indinavir, 15.6 μM; saquinavir, 24.0 μM; nelfinavir, 51.9 μM. In a clinical pharmacokinetic study, coadministration of ritonavir with DMI inhibited DMI clearance by an average of 59{\%}. The in vitro findings, together with observed plasma ritonavir concentrations, provided a reasonable quantitative forecast of this interaction, whereas estimated unbound plasma or intrahepatic ritonavir concentrations yielded poor quantitative forecasts. Thus the in vitro model correctly identifies ritonavir as a potent and clinically important inhibitor of human P450-2D6. Other protease inhibitors may also inhibit 2D6 activity in humans, but with lower potency than ritonavir.",
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