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Vol. 26, Issue 7, 609-616, July 1998
Agouron Pharmaceuticals Inc.
In vitro studies with human liver microsomes and P450
probe substrates were performed to characterize selectivity and
mechanism of cytochrome P450 inhibition by nelfinavir mesylate. At
therapeutic concentrations (steady-state plasma concentrations 
4
µM), nelfinavir was found to be a competitive inhibitor of only
testosterone 6
-hydroxylase (CYP3A4) with a
Ki concentration of 4.8 µM. At
supratherapeutic concentrations, nelfinavir competitively inhibited
dextromethorphan O-demethylase (CYP2D6),
S-mephenytoin 4-hydroxylase (CYP2C19), and phenacetin
O-deethylase (CYP1A2) with Ki
concentrations of 68, 126, and 190 µM, respectively. Nelfinavir did
not appreciably inhibit tolbutamide 4-hydroxylase (CYP2C9), paclitaxel
6
-hydroxylase (CYP2C8), or chlorzoxaxone 6-hydroxylase (CYP2E1)
activities. The inhibitory potency of nelfinavir toward CYP3A4
suggested the possibility of in vivo inhibition of this
isoform, whereas in vivo inhibition of other P450s was
considered unlikely. In a one-sequence crossover study in 12 healthy
volunteers, nelfinavir inhibited the elimination of the CYP3A substrate
terfenadine and the carboxylate metabolite of terfenadine. The 24-hr
urinary recoveries of 6-hydroxycortisol were reduced by an average
of 27% during nelfinavir treatment, consistent with CYP3A inhibition
by nelfinavir. Inhibition of CYP3A4 by nelfinavir in vitro
was NADPH-dependent requiring the catalytic formation of a metabolite
or a metabolic intermediate. The catechol metabolite of nelfinavir (M3)
was considered unlikely to be responsible for inhibition as the
addition of catechol O-methyl transferase,
S-adenosyl methionine, and ascorbic acid to the
preincubation mixture did not protect against the loss of testosterone
6-hydroxylase activity. Also, the addition of M3 to human liver
microsomes did not inhibit CYP3A4. Although incubations with nelfinavir
showed a time- and concentration-dependent loss of CYP3A4 activity, the partial or complete recovery of enzyme activity upon dialysis indicated
that inhibition was reversible. Microsomal incubations with nelfinavir
and NADPH did not result in a loss of spectral P450 content compared
with the NADPH control. Glutathione, N-acetylcysteine, and
catalase did not attenuate CYP3A4 inhibition by nelfinavir. Collectively, these results suggest that the probable mechanism for
CYP3A4 inhibition by nelfinavir is a transient metabolic intermediate or stable metabolite that coordinates tightly but reversibly to the
heme moiety of the P450.
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