|show drug details|
|159989-65-8 (MESYLATE SALT)|
|2-[2-HYDROXY-3-(3-HYDROXY-2-METHYL-BENZOYLAMINO)-4-PHENYL SULFANYL-BUTYL]-DECAHYDRO-ISOQUINOLINE-3-CARBOXYLIC ACID TERT-BUTYLAMIDE|
|3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2- [(2R,3R)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-(phenylthio)butyl]-, (3S,4aS,8aS)-|
|3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2-((2R,3R)-2-hydroxy-3-((3-hydroxy-2-methylbenzoyl)amino)-4-(phenylthio)butyl)-, (3S,4aS,8aS)-|
|3-Isoquinolinecarboxamide, N-(1,1-dimethylethyl)decahydro-2-(2-hydroxy-3-((3-hydroxy-2-methylbenzoyl)amino)-4-(phenylthio)butyl)-, (3S-(2-(2S*,3S*),3-alpha,4a-beta,8a-beta))-|
|AG1343 (*Mesylate salt*)|
|Met-SDF-1.beta. & Nelfinavir|
|Met-Stromal Cell-derived Factor-1.beta. (Human) & Nelfinavir|
|NELFINAVIR MESYLATE AG1343|
|Nelfinavir Monomethane Sulfonate|
|NSC722664 (MESYLATE SALT)|
|Viracept (*Mesylate salt*)|
|Ki: ||Kd:||Ic 50:||Ec50/Ic50:|
Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro.. Marika T Granfors; Jun-Sheng Wang; Lauri I Kajosaari; Jouko Laitila; Pertti J Neuvonen; Janne T Backman (2006) Basic & clinical pharmacology & toxicology display abstract
The effects of five HIV protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir and saquinavir) on cytochrome P450 (CYP) 3A4, 3A5 and 3A7 activities were studied in vitro using testosterone 6beta-hydroxylation in recombinant CYP3A4, CYP3A5 and CYP3A7 enzymes. The protease inhibitors showed differential inhibitory effects on the three CYP3A forms. Ritonavir and saquinavir were non-selective and preferential inhibitors of CYP3A4 and CYP3A5 (K(i) 0.03 microM and 0.6-0.8 microM for ritonavir and saquinavir, respectively), and weaker inhibitors of CYP3A7 (K(i) 0.6 microM and 1.8 microM, respectively). Nelfinavir was a potent and non-selective inhibitor of all three CYP3A forms (K(i) 0.3-0.4 microM). Amprenavir and indinavir preferentially inhibited CYP3A4 (K(i) 0.1 microM and 0.2 microM, respectively), with weaker inhibitory effects on CYP3A5 (K(i) 0.5 microM and 2.2 microM, respectively) and CYP3A7 (K(i) 2.1 microM and 10.6 microM, respectively). In conclusion, significant differences exist in the inhibitory potency of protease inhibitors for different CYP3A forms. Ritonavir, nelfinavir, saquinavir and amprenavir seem to be prone to drug-drug interactions by inhibiting both CYP3A4 and CYP3A5. Especially nelfinavir and ritonavir also have a potential to inhibit foetal CYP3A7-mediated drug metabolism and some endogenous pathways that may be crucial to normal foetal development, while indinavir has the lowest potential to inhibit CYP3A5 and CYP3A7.
Characterization of the selectivity and mechanism of human cytochrome P450 inhibition by the human immunodeficiency virus-protease inhibitor nelfinavir mesylate.. J H Lillibridge; B H Liang; B M Kerr; S Webber; B Quart; B V Shetty; C A Lee (1998) Drug metabolism and disposition: the biological fate of chemicals display abstract
In vitro studies with human liver microsomes and P450 probe substrates were performed to characterize selectivity and mechanism of cytochrome P450 inhibition by nelfinavir mesylate. At therapeutic concentrations (steady-state plasma concentrations approximately 4 microM), nelfinavir was found to be a competitive inhibitor of only testosterone 6beta-hydroxylase (CYP3A4) with a Ki concentration of 4. 8 microM. At supratherapeutic concentrations, nelfinavir competitively inhibited dextromethorphan O-demethylase (CYP2D6), S-mephenytoin 4-hydroxylase (CYP2C19), and phenacetin O-deethylase (CYP1A2) with Ki concentrations of 68, 126, and 190 microM, respectively. Nelfinavir did not appreciably inhibit tolbutamide 4-hydroxylase (CYP2C9), paclitaxel 6alpha-hydroxylase (CYP2C8), or chlorzoxaxone 6beta-hydroxylase (CYP2E1) activities. The inhibitory potency of nelfinavir toward CYP3A4 suggested the possibility of in vivo inhibition of this isoform, whereas in vivo inhibition of other P450s was considered unlikely. In a one-sequence crossover study in 12 healthy volunteers, nelfinavir inhibited the elimination of the CYP3A substrate terfenadine and the carboxylate metabolite of terfenadine. The 24-hr urinary recoveries of 6beta-hydroxycortisol were reduced by an average of 27% during nelfinavir treatment, consistent with CYP3A inhibition by nelfinavir. Inhibition of CYP3A4 by nelfinavir in vitro was NADPH-dependent requiring the catalytic formation of a metabolite or a metabolic intermediate. The catechol metabolite of nelfinavir (M3) was considered unlikely to be responsible for inhibition as the addition of catechol O-methyl transferase, S-adenosyl methionine, and ascorbic acid to the preincubation mixture did not protect against the loss of testosterone 6beta-hydroxylase activity. Also, the addition of M3 to human liver microsomes did not inhibit CYP3A4. Although incubations with nelfinavir showed a time- and concentration-dependent loss of CYP3A4 activity, the partial or complete recovery of enzyme activity upon dialysis indicated that inhibition was reversible. Microsomal incubations with nelfinavir and NADPH did not result in a loss of spectral P450 content compared with the NADPH control. Glutathione, N-acetylcysteine, and catalase did not attenuate CYP3A4 inhibition by nelfinavir. Collectively, these results suggest that the probable mechanism for CYP3A4 inhibition by nelfinavir is a transient metabolic intermediate or stable metabolite that coordinates tightly but reversibly to the heme moiety of the P450.
Inhibition of desipramine hydroxylation (Cytochrome P450-2D6) in vitro by quinidine and by viral protease inhibitors: relation to drug interactions in vivo.. L L von Moltke; D J Greenblatt; S X Duan; J P Daily; J S Harmatz; R I Shader (1998) Journal of pharmaceutical sciences display 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 Km value of 11.7 microM (range: 9.9-15.3 microM). 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 microM (range: 0.13-0.18 microM). 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 microM; indinavir, 15.6 microM; saquinavir, 24.0 microM; nelfinavir, 51.9 microM. 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.