TY - JOUR
T1 - Inhibition of desipramine hydroxylation (cytochrome P450-2D6)in vitro by quinidine and by viral protease inhibitors
T2 - Relation to drug interactions in vivo
AU - Von Moltke, Lisa L.
AU - Greenblatt, David J.
AU - Duan, Su Xiang
AU - Daily, Johanna P.
AU - Harmatz, Jerold S.
AU - Shader, Richard I.
N1 - Funding Information:
This work was supported by Grants MH-34223, MH-19924, and RR-00054 from the USPHS, and by Grant DA-50038 from the Department of Veterans Affairs and the National Institute on Drug Abuse supporting the Medication Development and Research Unit, Boston VA Medical Center and Boston University School of Medicine. Dr. von Moltke is the recipient of a Scientist Development Award (K21-MH-01237) from the National Institutes of Mental Health.
PY - 1998/10
Y1 - 1998/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0031667738&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031667738&partnerID=8YFLogxK
U2 - 10.1021/js980197h
DO - 10.1021/js980197h
M3 - Article
C2 - 9758674
AN - SCOPUS:0031667738
SN - 0022-3549
VL - 87
SP - 1184
EP - 1189
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 10
ER -