Inhibition of CYPs

The experiment was conducted in the presence of the fungus and the compound ABT at sufficiently high concentration, 5 mM, to cause the inhibition of Cyp P450 enzyme system expression by the fungus. 

Association to allopurinol, amiodarone, fluoroquinolones, carbamazepine, pheno-barbital, rifampicin, and others Inhibition of CYP activity by the drugs... 

Naphthyl inhibitor 38 (Kj = 500 nM) was discovered via a displacement-based HTS assay utilizing radiolabeled (R)-NPTS [77]. However, compound 38 demonstrated high affinity for 5-HT1B (Kj < 1 nM), hERG (K, = 1.2 iM), significant inhibition of CYP 2D6, and poor microsomal stability. 

For all intent and purpose, inhibition of CYP enzymes can be classified into two categories reversible (e.g. competitive and noncompetitive) inhibition and mechanism-based (e.g. quasi-irreversible and irreversible) inhibition [93]. The remainder of this chapter will be divided to reflect these two categories of inhibition and will focus solely on CYP-based drug interactions. 

Irreversible inhibition of CYPs is particularly worrisome as its consequences cannot be predicted easily or quantified from in vitro data the in vivo effect of an irreversible inhibitor is usually greater than that predicted based on affinity alone. Moreover, irreversible inhibition is generally the consequence of the production of reactive metabolites (electrophiles), which can also bind covalently to endogenous proteins and, in rare cases, trigger serious autoimmune reactions [4]. 

Due to high chance of drug interactions through inhibition of CYP 3A4, use caution with any additional drugs... 

Flavonoids, especially flavones and flavonols, also directly bind to several CYP isoforms (lAl, 1A2, IBl, 3A4) involved in xenobiotics metabolism and inhibit enzyme activity. Structure-activity relationships show rather high isoform selectivities depending on the flavonoid substitution pattern and contrasted inhibition mechanisms. For instance, inhibition by flavonoids of 7-methoxyresorufin O-demethylation in microsomes enriched in CYP lAl and 1A2 reveals that galangin (3,5,7-trihydroxyflavone) is a mixed inhibitor of CYP 1A2 (.ST = 8 nM) and a five times less potent inhibitor of CYP 1A1. By contrast, 7-hydroxy flavone is a competitive inhibitor of CYP lAl (Aii = 15 nM) and a six times less potent inhibitor of CYP 1A2. In addition, fairly selective inhibition of CYP IBl (specifically detected in cancer cells) by some flavonoids has been reported. For example, 5,7-dihydroxy-4 -methoxyflavone inhibits IBl, 1 Al, and 1A2 with IC50 values of 7, 80, and 80 nM, respectively. ... 

Atomoxetine has not been shown to exert clinically significant inhibition of CYP 1A2, CYP 2C9, CYP 2D6, and CYP 3A isoenzymes (Sauer et al. 2004). However, paroxetine, a potent CYP 2D6 inhibitor, has been shown to increase plasma concentrations of atomoxetine and significantly increase the half-life of atomoxetine approximately 2.5-fold in extensive 2D6 metabolizers (Belle et al. 2002). Caution should be used when administering atomoxetine to patients taking albuterol or pressor agents because atomoxetine may potentiate the cardiovascular effects of albuterol or pressor agents. 

Disadvantages of nefazodone include the need for a twice-a-day dosing schedule and dose adjustment. Work is under way to develop a once-a-day sustained release version of nefazodone. The fact that nefazodone must be started at a lower than usually effective dose and then adjusted to an effective dose is a distinct disadvantage. That is made even more problematic because arguably more variability exists among patients in terms of the optimal dose of nefazodone as far as efficacy and tolerability than for virtually any other antidepressant. Finally, nefazodone produces substantial inhibition of CYP 3A3/4, leading to the potential for adverse pharmacokinetic interactions as well as possible unknown long-term consequences. 

The sum of the concentration of venlafaxine and ODV is probably more important than their relative ratio. Thus, CYP 2D6 deficiency, which occurs in approximately 7% of Caucasians, has fewer clinical implications for venlafaxine than for drugs that are biotransformed by this isoenzyme to either centrally inactive metabolites (e.g., paroxetine) or metabolites that have a different pharmacological profile than the parent drug (e.g., TCAs). The increase in venlafaxine plasma levels is offset by a parallel decline in ODV levels such that the sum is the same. Nevertheless, a substantial inhibition of CYP 3A3/4 could result in a meaningful increase in both venlafaxine and ODV plasma levels, particularly in patients who are CYP 2D6 deficient. Such an increase would be expected to result in an increase in the incidence or severity of the known dose-dependent effects of venlafaxine mediated by its inhibition of the neuronal uptake pumps for serotonin and NE. 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

Venlafaxine is converted by CYP 2D6 to ODV, which is subsequently cleared by CYP 3A3/4 ( 501). ODV has virtually the same in vitro pharmacology as venlafaxine. Thus, the total of venlafaxine plus ODV is believed to be the relevant concentration determining clinical effect ( 137). Theoretically, venlafaxine should be relatively impervious to even substantial CYP 2D6 inhibition because ODV levels would decrease proportionate to the increase in venlafaxine levels such that the total level would remain the same. In contrast, the inhibition of CYP 3A3/4 would be potentially more clinically relevant because it should decrease ODV clearance and thus increase total levels. Nevertheless, such an interaction would not be expected to do more than increase the usual dose-dependent adverse effects of venlafaxine because of its wide therapeutic index. 

Because of its substantial inhibition of CYP 3A3/4, this antidepressant is prone to pharmacokinetic drug-drug interactions with substrates for this enzyme ( Table 7-30). That is important because CYP 3A3/4 is responsible for approximately 50% of all known drug metabolism. Thus, there are a number of medications that either... 

Dong quai Coumarin constituents inhibition of platelet aggregation possible inhibition of CYP isoenzymes Increased INR and PT no bleeding episode in one case widespread bruising in another report ... 

Scheme 3.6 Piperonyl butoxide (PBO), a pesticide synergist, and PBO suicide inhibition of CYP. Modified from [49].

Studies with isolated rat hepatocytes have indicated that at least three CYP isoenzymes (2E1,2B1 and lAl/2) are involved in the detoxication of hydrazine, as inducers of these isoenzymes all reduce its cytotoxicity. Pretreatment of rats with diethyl-dithiocarbamate increased the cytotoxicity of hydrazine, this being associated with marked inhibition of CYP activities (Delaney Timbrell, 1995). 

Table 3 Structures Associated with Metabolism-Dependent Inhibition of CYP Enzymes...

Table 7 Inhibition of CYP Enzymes in Pooled Human Liver Microsomes by Direct Inhibitors (Positive Controls)... 

Chloramphenicol and secobarbital exhibit properties similar to those of tienilic acid, but they have not been studied in humans (11). Oxidative dechlorination of chloramphenicol with formation of reactive acyl chlorides appears to be an important metabolic pathway for irreversible inhibition of CYP. Chloramphenicol binds to CYP, and subsequent substrate hydroxylation and product release are not impaired. The inhibition of CYP oxidation and the inhibition of endogenous NADPH oxidase activity suggest that some modification of the CYP has taken place, which inhibits its ability to accept electrons from the CYP reductase (11). Secobarbital completely inactivates rat CYP2B1 functionally, with partial loss of the heme chromophore. Isolation of the N-alkylated secobarbital heme adduct and the modified CYP2B1 protein revealed that the metabolite partitioned between heme N-alkylation, CYP2B1 protein modification, and epoxidation. A small fraction of the prosthetic heme modifies the protein and contributes to the CYP2B1 inactivation (12). 

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