Sj. Porter et al., Kinetics and inhibition of the formation of 6 beta-naltrexol from naltrexone in human liver cytosol, BR J CL PH, 50(5), 2000, pp. 465-471
Aims To determine the kinetics of the formation of 6 beta -naltrexol from n
altrexone in human liver cytosol, and to investigate the role of potential
inhibitors.
Methods The kinetics of the formation of 6 beta -naltrexol from naltrexone
were examined in eight human liver cytosol preparations using h.p.l.c. to q
uantify 6 beta -naltrexol and, the extent of inhibition of 6 beta -naltrexo
l formation was determined using chemical inhibitors. The formation of 6 be
ta -naltrexol and the back reaction of 6 beta -naltrexol to naltrexone were
also examined in a microsomal preparation.
Results The V-max, K-m and CLint values for the formation of 6 beta -naltre
xol from naltrexone were in the ranges of 16-45 nmol mg(-1) protein h(-1),
17-53 mum and 0.3-2.2 ml h(-1) mg(-1) protein, respectively. The steroid ho
rmones testosterone (K-i = 0.3 +/- 0.1 mum) and dihydrotestosterone (K-i =
0.7 +/- 0.4 mum) were the most potent competitive inhibitors of 6 beta -nal
trexol formation, with naloxone, menadione and corticosterone also producin
g > 50% inhibition at a concentration of 100 mum. The opioid agonists morph
ine, oxycodone, oxymorphone and hydromorphone, and a range of benzodiazepin
es showed < 20% inhibition at 100 mum. In the microsomal preparation, there
was no formation of naltrexone from 6 beta -naltrexol nor any formation of
6 beta -naltrexol from naltrexone.
Conclusion The intersubject variability in the kinetic parameters of 6 beta
-naltrexol formation could play a role in the efficacy of and patient comp
liance with naltrexone treatment. This variability could be due in part to
a genetic polymorphism of the dihydrodiol dehydrogenase DD4, one of the enz
ymes reported to be responsible for the formation of 6 beta -naltrexol from
naltrexone. DD4 also has hydroxysteroid dehydrogenase activity which could
account for the potent inhibition by the steroid hormones testosterone and
dihydrotestosterone. The clinical significance of the latter finding remai
ns to be established.