Screening for Cytochrome P450 3A in Man: Studies with Midazolam and Nifedipine

Abstract

This report describes work directed towards the development of a screening technique for cytochrome P450 3A activity which should be valid for a variety of drugs metabolized by this enzyme. A significant correlation (P < 0.01) was found between the ratio of the plasma concentration of nifedipine to that of its oxidized metabolite and the area under the time curve for the plasma concentration of midazolam. It is suggested that the nifedipine: metabolite ratio might have general predictive value for the metabolism of orally administered cytochrome P450 3A substrates.

In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam

“…From this, it has been inferred that, notwithstanding the differences in selectivity of the pathways of hydroxylation, they interact with a common ligand‐binding domain within the CYP3A4 catalytic pocket. Accordingly, it was postulated that interrelationships between the clearances of the selected drugs (ie, the ability to predict the clearance of one CYP3A substrate from that of another) would be more robust than if the comparison involved drugs that interacted with different domains within the catalytic site, as might have been the case in previous and largely unsuccessful studies 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 …”

“…Surprisingly, only a very limited number of studies have actually investigated the relationship between one CYP3A in vivo probe to that of another with the use of a direct trait measure of metabolism. With the exclusion of the ERBT, in most other cases, indirect and probably flawed phenotypic traits have been used (eg, the urinary dapsone recovery ratio, 9 , 11 the urinary dextromethorphan/methoxymorphinan ratio, 14 and the plasma nifedipine dehydro [M1] metabolite ratio 13 ). In the case of lidocaine clearance, a highly significant relationship was found (r s = 0.9, P < .01) with midazolam after intravenous administration of both drugs; however, this correlation disappeared after CYP3A inhibition by erythromycin 17 .…”

“…Several in vivo probes have been used for this purpose, including erythromycin (breath test), dapsone, cyclosporine (INN, ciclosporin), endogenous cortisol, nifedipine, lidocaine, dextromethorphan, alprazolam, and midazolam 3 , 4 , 5 , 6 . However, the correlations between pairs of the various presumed trait measures of CYP3A‐mediated metabolism have, in general, been remarkably poor, given the presumed involvement of a common enzyme 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 …”

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

“…However, an as yet unexplained situation apparently exists in vivo whereby only relatively weak correlations have been found between various phenotypic trait measurements of CYP3A activity (212)(213)(214), and the ability of any such test to accurately predict the clearance of another CYP3A substrate has generally been poor (214,(232)(233)(234)(235)(236). In certain instances, this may be because some in vivo probes are not as valid as previously considered, e.g.…”

Lack of In Vivo Correlation Between Indinavir and Saquinavir Exposure and Cytochrome P450 3A Phenotype as Assessed with Oral Midazolam as a Phenotype Probe

“…In general, most studies have not demonstrated a strong correlation between purported CYP3A probes. [4][5][6][7][8][9][10][11][12][13] The clearance of intravenous midazolam was correlated with hepatic CYP3A content and with the clearance of intravenous cyclosporine in patients receiving liver transplants. 1,2 However, in subsequent studies, clearances of oral midazolam and cyclosporine were poorly correlated, as were the clearance of intravenous midazolam and results of the erythromycin breath test.…”