Warfarin CYP2C9 substrate

Aripiprazole 10 to 30 mg daily had no significant effects on the metabolism of dextromethorphan (CYP2D6 and CYP3A4 substrate), warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate). Aripiprazole is not expected to affect CYPl A2-mediated metabolism. The manufacturers therefore conclude that aripiprazole is unlikely to have clinically significant interactions with drugs that are substrates for these isoenzymes. ... 

FIGURE 4.11 Structures of the CYP2C9 substrates, warfarin, tolbutamide, (S (-flurbiprofen, and diclofenac, and their metabolites. 

Aprepitant may be affected by paroxetine, CYP2C9 substrates (eg, phenytoin, tolbutamide, warfarin), CYP3A4 substrates (eg, alprazolam, cisapride, dexamethasone, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, methylprednisolone, midazolam, paclitaxel, pimozide, triazolam, vinblastine, vincristine, vinorelbine), and oral contraceptives. 

A77 1726 inhibits CYP2C9 and might increase the systemic availabihty of CYP2C9 substrates, such as warfarin and phenytoin (97,98). 

Attention is warranted when certain sulfonamides (for example sulfaphenazole, sulfadiazine, sulfamethizole, and sulfafurazole) are co-administered with CYP2C9 substrates with narrow therapeutic ranges, such as warfarin (215). 

Drug interactions May decrease antihypertensive effects of ACE inhibitors and angiotensin II antagonists decrease of antihypertensive and diuretic effects of thiazides and loop diuretics Agents are CYP2C9 substrates may decease effects of ACE inhibitors, thiazides, and loop diuretics fluconazole Increases levels of celecoxib may increase INR when added to warfarin... 

The angiotensin II antagonists, and warfarin, are substrates for the cytochrome P450 isoenzyme CYP2C9. It was therefore possible that they might affect warfarin metabolism. However, this does not appear to happen. 

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. 

The manufacturers advise caution if leflunomide is given with phenytoin or tolbutamide. The reason is that the active metabolite of leflunomide (A771726) has been shown by in vitro studies to be an inhibitor of the cytochrome P450 isoenzyme CYP2C9, which is concerned with the metabolism of these two drugs. If this inhibition were to occur in vivo it could possibly lead to a decrease in their metabolism and an increase in their toxicity. Although so far there appear to be no clinical reports of an interaction, the manufacturers made a similar prediction with warfarin, another CYP2C9 substrate, which has, in isolated cases, been borne out in practice. See Coumarins + Leflunomide , p.423. 

Metronidazole Nausea/vomiting Metallic taste Refrain from using alcoholic beverages potential for disulfiram-like reaction Substrate for CYP2C9 and inhibitor of CYP2C9, 3A3/4 and 3A5-7 potential interactions may include warfarin (enhanced prothrombin time) and lithium (increased concentrations)... 

Figure 9.3 The effects of varying levels of accessory proteins on CYP2C9 kinetics using diclofenac (a) or (S)-warfarin (b) as substrate probe [219].

Fig. 14.8 Experimental ligand interactions with cytochrome P450 2C family. (A) X-ray structure ofthe sulfaphenazole derivate DMZ in rabbit CYP2C5 at 2.3 A resolution (PDB 1 N5B) from Wester et al. [191]. Only one ofthe two-ligand orientations for DMZ in accord with electron density is shown placing the benzylic methyl group in a 4.4 A distance to the heme iron. (B) X-ray structure of S-warfarin in human CYP2C9 at 2.55 A resolution (PDB 10G5) from Williams et al. [192]. The substrate is situated in a predominantly hydrophobic pocket. This binding mode places the 6- and 7-hydroxylation sites 10 A from the iron (arrow).

Haining, R. L., Jones, J. R, Henne, K. R., et al. (1999) Enzymatic determinants of the substrate specificity of CYP2C9 role of B -C loop residues in providing the pi-stacking anchor site for warfarin binding. Biochemistry 38, 3285-3292. 

Substrates CYP2C9 Most NSAIDs (including COX-2), warfarin, phenytoin... 

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