Carbamazepine metabolic pathway

The major metabolic pathway of carbamazepine is an example of this oxidation as shown in Figure 4.73. The usual bond angle of a sp3-hybridized carbon is 109°, but it is constrained to be 60° in an epoxide making epoxides reactive. This reactivity varies significantly depending on the structure of the epoxide, and this will be discussed further in Chapter 8. The epoxide of carbamazepine is relatively unreactive and easy to isolate. 

As a metabolic pathway, alkene oxidation is not common. When an alkene is oxidized, an epoxide forms. The epoxide normally reacts with water and opens to a 1,2-diol. The alkene in carbamazepine (8.20) is oxidized to a small degree to form the corresponding epoxide (8.21) (Scheme 8.7). 

ALMOTRIPTAN, ELETRIPTAN CARBAMAZEPINE Possible 1 plasma concentrations of almotriptan and risk of inadequate therapeutic efficacy. Risk of serotonin syndrome One of the major metabolizing enzymes of almotriptan - CYP3A4 isoenzymes - is induced by rifampicin. As there are alternative metabolic pathways, the effect may not be significant and can vary from individual to individual. Triptans and carbamazepine are both stimulants of 5-HT receptors, and carbamazepine in addition prevents the reuptake of 5-HT Be aware of possibility of l response to triptan, and consider T dose if considered to be due to interaction. Be aware of the possibility of the occurrence of serotonin syndrome >- For signs and symptoms of serotonin toxicity, see Clinical Features of Some Adverse Drug Interactions, Serotonin toxicity and serotonin syndrome... 

Fig. 17 Metabolic pathway of carbamazepine in humans, physicochemical descriptors, and toxicity model. Physicochemical properties are from (a) Physprop database www.syrres.com, (b) estimated with fragment method according to [11], (c) [62], (d) [63]...

Skin Oxcarbazepine is considered to be much less likely than carbamazepine to cause skin reactions, owing to its different metabolic pathway. Oxcctrbazepine-associated Stevens-Johnson syndrome has been described in two Chinese patients with epilepsy, one of whom was positive for HLA-B 1502 [223, 224 ]. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

Special attention is needed when new medications are prescribed to CSA-treated patients. CSA is extensively metabolized by the cytochrome P450 hver microsomal enzyme system [2, 3], and consequently drugs that interfere with this pathway can cause important changes in CSA blood levels (Table 3). Compounds inhibiting P450 enzymes, such as ketoconazole, erythromycin, verapamil, and diltiazem increase concentration of parent CSA and may cause acute nephrotoxicity. On the other hand, drugs that increase P450 enzyme activity, such as phenobarbital, carbamazepine and... 

Danazol inhibits the metabolism (by the epoxide-trans-diol pathway) of carbamazepine by the liver, thereby reducing its loss from the body. During danazol treatment the clearance of carbamazepine has been found to be reduced by 60%. ... 

---