Enzyme induction and inhibition

Barry, Michael; Feely, J.

doi:10.1016/0163-7258(90)90019-x

Cited by 75 publications

(46 citation statements)

References 212 publications

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“…Assuming that the persistent metabolic effect we estimate is real, one possible mechanism for it is irreversible inactivation of the CYP3A4 enzyme responsible for S metabolism by R, possibly through the formation of metabolic intermediate complexes (Koudriakova et al, 1998). Return of metabolic capacity with such a mechanism would occur at a rate governed by the resynthesis rate of the relevant CYP3A4, rather than by the disappearance rate of plasma R, and this is compatible with our estimated 30-h half-life of persistence (Barry and Feely, 1990;Li et al, 1997). Although R (and N) are known to be (rapidly) reversible competitive inhibitors of CYP3A4 (Kempf et al, 1997;Lillibridge et al, 1998), that does not rule out an irreversible component as well.…”

Section: Ritonavir Nelfinavir and Saquinavir Interactionssupporting

confidence: 74%

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Blaschke

Flexner³

et al. 2002

Drug Metab Dispos

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ABSTRACT:Eighteen healthy human immunodeficiency virus-negative subjects participated in an open-label, six-period, incomplete Latinsquare crossover pharmacokinetic study. Each subject received two of the three possible pair-wise combinations of single-dose oral ritonavir (R) (400 mg), nelfinavir (N) (750 mg), and saquinavir (S) (800 mg), each pair on three occasions (simultaneous or staggered administration), each occasion at least 2 days after the last. A model-based analysis reveals the following major drug interactions under the conditions of this study: 1) R given simultaneously with S decreases S hepatic intrinsic clearance almost 50-fold relative to that predicted for S given alone and increases its gut bioavailability 90% (but decreases its rate of absorption 40%) relative to when N is given simultaneously; 2) N given simultaneously with S decreases S hepatic intrinsic clearance 10-fold relative to that predicted for S given alone; and 3) R inhibits S hepatic intrinsic clearance even after R plasma levels have become undetectable (>48 h after dosing), implying that R, when used as a pharmacokinetic enhancer, can be dosed less frequently than might be predicted from the duration of detectable systemic concentrations.Protease inhibitors (PIs 1 ) ritonavir (R), nelfinavir (N), and saquinavir (S) are primarily metabolized by CYP3A4 (and partially by other cytochromes P450) in the liver (Eagling et al., 1997;Fitzsimmons and Collins, 1997;Hsu et al., 1998a;Kim et al., 1998;Washington et al., 1998). They exhibit extensive pharmacokinetic (PK) interactions (Merry et al., 1997;Hsu et al., 1998b;Jarvis et al., 1998), but the degree to which those interactions occur at the level of hepatic metabolism, gut metabolism, or gut efflux transporters is still uncertain. Adult AIDS clinical trial group study 378 (ACTG 378), involving staggered versus simultaneous administration of the three PIs, was designed to shed light on these issues. The findings with respect to changes of AUC (proportional to the ratio of systemic clearance to bioavailability) are reported elsewhere (C. B. Washington, C. Flexner, L. B. Sheiner, S. L. Rosenkranz, M.A. Jacobson, T. F. Blaschke, submitted); they are considerable. This paper extends those findings by presenting a physiologically based population pharmacokinetic model applied to the full ACTG 378 data to assess and quantify the gut versus hepatic mechanisms responsible for the AUC changes and for any other PK interactions. Materials and MethodsData Source. ACTG 378 was an open-label, Latin-square design study of the effect of staggered versus simultaneous dosing on the PK profiles of the following three protease inhibitors: R, N, and S (we use the symbols R, N, S to refer not only to the drugs but to their concentrations; context should make clear which meaning is intended). A total of 18 human immunodeficiency virus-negative healthy volunteers participated in the study, and each was randomized to receive two of the three pairs (N ϩ R, N ϩ S, and R ϩ S) in two series of three occasions. T...

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Section: Ritonavir Nelfinavir and Saquinavir Interactionssupporting

confidence: 74%

Model-based Analysis of the Pharmacokinetic Interactions Between Ritonavir, Nelfinavir, and Saquinavir after Simultaneous and Staggered Oral Administration

Blaschke

Flexner³

et al. 2002

Drug Metab Dispos

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“…Since many P450 isoforms are involved in the metabolism of TCAs, it is not surprising that numerous interactions between TCAs and enzyme inducers or inhibitors have been described (Barry and Feely, 1990;Tanaka and Hisawa, 1999). Except for one report of moderate inhibition of CYP2D6-catalyzed codeine O-demethylation (Yue and Säwe, 1997), however, the inhibitory potential of TCAs on different P450 isoforms has not been extensively described.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effects of Tricyclic Antidepressants (TCAs) on Human Cytochrome P450 Enzymes in Vitro: Mechanism of Drug Interaction between TCAs and Phenytoin

Shin¹,

Park²,

Kim³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The ability of tricyclic antidepressants (TCAs) to inhibit phenytoin p-hydroxylation was evaluated in vitro by incubation studies of human liver microsomes and cDNA-expressed cytochrome P450s (P450s). The TCAs tested were amitriptyline, imipramine, nortriptyline, and desipramine. Amitriptyline and imipramine strongly and competitively inhibited phenytoin p-hydroxylation in microsomal incubations (estimated K i values of 5.2 and 15.5 M, respectively). In contrast, nortriptyline and desipramine produced only weak inhibition. In the incubation study using cDNA-expressed P450s, both CYP2C9 and CYP2C19 catalyzed phenytoin p-hydroxylation, whereas TCAs inhibited only the CYP2C19 pathway. All of the TCAs tested inhibited CYP2D6-catalyzed dextromethorphan-O-demethylation competitively, with estimated K i values of 31.0, 28.6, 7.9, and 12.5 M, respectively. The tertiary amine TCAs, amitriptyline and imipramine, also inhibited CYP2C19-catalyzed S-mephenytoin 4-hydroxylation (estimated K i of 37.7 and 56.8 M, respectively). The secondary amine TCAs, nortriptyline and desipramine, however, showed minimal inhibition of CYP2C19 (estimated IC 50 of 600 and 685 M, respectively). None of the TCAs tested produced remarkable inhibition of any other P450 isoforms. These results suggest that TCAs inhibit both CYP2D6 and CYP2C19 and that the interaction between TCAs and phenytoin involves inhibition of CYP2C19-catalyzed phenytoin p-hydroxylation.

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“…SQV is metabolised by CYP3A4 and so has the potential to interact with drugs that either induce or inhibit this enzyme [201]. Induction of SQV is particularly important as many patients are believed to have SQV plasma levels near or below the minimum effective concentrations [204]. Co-administration of inducers of CYP 3A4 increase metabolism resulting in decreases in steady-state AUC and peak plasma concentration (C max ) of SQV.…”

Section: Saquinavir (Sqv)mentioning

confidence: 99%

“…Also, addition of an inhibitor of CYP3A4 to an IDV regimen leads to an increase in IDV concentrations. On the other hand, patients treated with inducers of this enzyme, such as phenobarbital or rifabutin, result in decreased IDV concentrations [204].…”

Section: Indinavir (Idv)mentioning

confidence: 99%