Cocaine N-demethylation to norcocaine was studied in human liver microsomes of different ages. Norcocaine was formed at a considerable rate in fetal (45.4 ± 18.2 nmol/mg X hour, n = 8) and adult specimens (82.0 ± 46.6 nmol/mg X hour, n = 15), p=0.04 (Mann-Whitney). Furthermore, the apparent Km values in fetal specimens (0.57 and 0.48 mM, n = 2) showed a higher affinity compared with those of adults (mean value 2.7 (1.8-4.25) mM, n = 4). Estimated enzyme metabolic clearance with respect to P450 total content was higher in fetal than in adult liver microsomes (2.22 ml/nmol P450 X hour, and 0.18 (0.14-0.23) ml/nmol P450 X hour, respectively). Several drugs, known to be CYP3A substrates, were used as potential inhibitors of cocaine metabolism. Midazolam, ergotamine and erythromycin showed strong inhibition (approx. 70%) when used at concentrations of 500 μM (midazolam, erythromycin) or 200 μM (ergotamine). The metabolism of 1 mM cocaine correlated strongly with immunodetected CYP3A protein determined by Western blotting in both fetal (r = 0.89, p =0.19) and adult specimens (r = 0.82, p<0.01). These findings further support CYP3A as a major catalyst of norcocaine formation in human liver microsomes. These results are important given the potential risk of toxicity to the foetus of maternal cocaine abuse during pregnancy. Although the high Km values found in adult livers reduce the importance of this enzyme pathway in cocaine detoxication, this pathway would emerge as significant in circumstances of CYP3A induction and/or drug interactions leading to potential liver toxicity in chronic cocaine abusers. © 2000 Elsevier Science Inc.
|Publication status||Published - 15 Dec 2000|
- Cocaine metabolism
- Enzyme kinetics
- Human developmental metabolism
- Human fetus
- Human liver microsomes