Cytochrome P450 enzymes profiling

Species differences in the metabolism of di(2-ethylhexyl) phthalate have been reported and attempts have been made to explain the susceptibility of animals to di(2-ethylhexyl) phthalate-induced hepatic peroxisome proliferation based on their metabolic profiles (Doull et al., 1999). As mentioned above, the bulk of a di(2-ethylhexyl) phthalate dose is absorbed as the mono-ester, mono(2-ethylhexyl) phthalate, and following absorption this metabolite is subjected to extensive oxidative metabolism mediated by cytochrome P450 enzymes (Albro Lavenhar, 1989 Astill, 1989 Huber et al., 1996 Doull et al., 1999). The metabolism of mono(2-ethylhexyl) phthalate has been summarized by Doull et al. (1999) as follows (see Figure 1) ... 

Rifapentine is an analog of rifampin. It is active against both M tuberculosis and Mavium. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine is indicated for treatment of tuberculosis caused by rifampin-susceptible strains. The dose is 600 mg once or twice weekly. Whether rifapentine is as effective as rifampin has not been established, and rifampin therefore remains the rifamycin of choice for treatment of tuberculosis. 

Figure 16 Variability in promiscuous activities caused by mutations in a cytochrome P450 enzyme that had been evolved to hydroxylate12-p-nitrophenoxydodecanoic acid (12-pNCA). The 34 variants listed on the right are clustered according to their activity profiles. PROP, propranolol 2A5C, 2-amino-5-chlorobenzoxazole MDOB, 1,2-methylenedioxybenzene 2PE, 2-phenoxyethanol 11 PA, 11-phenoxyundecanoic acid. Reproduced with permission from J. D. Bloom P. A. Romero Z. Lu F. H. Arnold, Biol. Direct 2007, 2, 17.

All the SSRIs have similar spectrums of efficacy and similar side-effect profiles. However, they are structurally and in some instances clinically distinct. For example, allergy to one SSRI does not predict allergy to another. Similarly, response or nonresponse to one SSRI does not necessarily predict a similar reaction to another medication in the class. SSRIs also have distinct pharmacokinetic properties, the most important of which are differences in half-life (Table 2-1) and the propensity to inhibit cytochrome P450 (CYP) enzymes (Table 1-1). 

---