Cytochrome P450 isoenzyme substrates

Bitter orange + Cytochrome P450 isoenzyme substrates... 

Metabolism is still a barrier to be overcome. Some QSAR, pharmacophore, protein, and rule-based models are available to predict substrates and inhibitors of a specific cytochrome P450 isoenzyme [47-55]. 

Memantine is not a major substrate for hepatic cytochrome P450 isoenzymes and has not been shown to significantly inhibit or induce these enzymes. However, memantine is partially excreted by renal tubular secretion. Thus, concomitant use of other medications that use the same renal system (i.e., triampterene, hydrochlorothiazide, digoxin, cimetidine, ranitidine, metformin, and quinidine) may affect plasma levels of both drugs (Namenda 2005). Memantine should not be used in combination with other NMDA receptor antagonists, such as amantadine or dextromethorphan, because these combinations have not been formally studied. The clearance of memantine can be reduced when the urine is alkalinized, such as with the concomitant use of sodium bicarbonate or carbonic anhy-... 

Zaleplon is primarily metabolized by aldehyde oxidase and use with inhibitors of this enzyme, such as cimetidine, may result in increased plasma concentrations of zaleplon. Zaleplon is also partly metabolized by the cytochrome P450 isoenzyme CYP3A4 and, consequently, caution is advised when zaleplon is given with drugs that are substrates for, or potent inhibitors of, this isoenzyme. Cimetidine is also an inhibitor of CYP3A4 and thus inhibits both the primary and secondary metabolic pathways of zaleplon. Use with rifampicin or other potent enzyme-inducing drugs may accelerate the metabolism of zaleplon and reduce its plasma concentrations [40]. 

Smith, D. A., Ackland, M. J., and Jones, B. C. Properties of cytochrome P450 isoenzymes and their substrates. Part 1 Active site characteristics. Drug Discovery Today 2 406-414, 1997. 

Table 30.4 Nonexhaustive list of substrates for, and inducers and inhibitors of some human liver cytochrome P450 isoenzymes...

Both phenytoin and losartan are substrates for the cytochrome P450 isoenzyme CYP2C9. It appears that phenytoin had an inhibitory effect on losartan metabolism. The conversion of losartan to E3174 represents about 5 to 15% of the clearance of an oral losartan dose, but E3174 is much more active than losartan. 

Buprenorphine is a substrate for the cytochrome P450 isoenzyme CYP3A4 and inducers of CYP3A enzymes such as efavirenz would be expected to increase buprenorphine clearance, whereas delavirdine, which is an inhibitor of CYP3A, would be expected to reduce the CYP3A-mediated metabolism of buprenorphine to norbuprenorphine. 

Not established. A possible reason is that isoniazid induces the cytochrome P450 isoenzyme CYP2E1 by stabilisation. This means that while the isoniazid is still present, the metabolism of substrates such as paracetamol is inhibited. However, when isoniazid levels drop sufficiently (as may be the case late in the dosing interval in fast acetylators), metabolism may be induced resulting in a greater proportion of the paracetamol being converted into toxic metabolites than would normally occur. ... 

Modafinil is an inducer of the cytochrome P450 isoenzyme CYP3A4. The manufacturers therefore predict that it may reduce the levels of drugs that are CYP3A4 substrates. They specifically name the protease inhibitors, buspirone, calcium-channel blockers, ciclosporin, midazolam, and the statins [note that only some statins, namely atorvastatin, lovastatin and... 

Fluconazole and voriconazole almost certainly cause a rise in omeprazole and esomeprazole levels by inhibiting their metabolism by the cytochrome P450 isoenzymes CYP2C19 and CYP3A4. As esomeprazole is an inhibitor of and also a substrate for CYP2C19, it is likely to have the same effect as omeprazole. Ketoconazole only inhibits CYP3A4 and therefore causes a less marked rise in omeprazole levels. Itraconazole would be expected to interact similarly to ketoconazole. 

Not known. Based on in vitro data, both entacapone and tolcapone were thought to potentially interfere with the metabolism of drugs by the cytochrome P450 isoenzyme CYP2C9, such as 5-warfarin. " However, the above study shows that entacapone does not alter 5-warfarin pharmacokinetics, and tolcapone is also thought not expected to interact by this mechanism because it does not interact with tolbutamide , (p.516), another CYP2C9 substrate. 

Some NSAIDs are inhibitors of the cytochrome P450 isoenzyme CYP2C9, and inhibit the metabolism of warfarin via this isoenzyme. There is also possibly a pharmacokinetic interaction with NSAIDs that are substrates for CYP2C9. People with variant CYP2C9 (about 5 to 11% of Caucasians) have a lower metabolising capacity for warfarin, and require much lower maintenance doses. It is possible that use of an NSAID that is a CYP2C9 substrate may result in reduced warfarin metabolism, although this requires confirmation in controlled studies. 

Not understood. The effect dextropropoxyphene has on the metabolism of the warfarin enantiomers does not appear to have been studied. Dextropropoxyphene does not interact with other cytochrome P450 isoenzyme CYP2C9 substrates such as tolbutamide , (p.486), although it does interact with the CYP3A4 substrate carbamazepine , (p.527). There is also the possibility that the paracetamol component had some part to play (see also Coumarins + Paracetamol (Acetaminophen) , p.438). Alternatively, these eases may just represent idiosyncratic reactions. 

Metabolism of diazepam to A -desmethyl-diazepam occurs via the cytochrome P450 isoenzyme CYP2C19, and in vitro studies had shown that melagatran was a weak inhibitor of this isoenzyme. However, the lack of a pharmacokinetic interaction with diazepam suggests that no clinically relevant interaction occurs, and is also unlikely with other CYP2C19 substrates (for a list see Table 1.3 , (p.6)). 

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