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Corpus ID: 91874052

The Role of Cytochrome

P450 3A Inducers and
Inhibitors in the Metabolism
and the Effects of
Oxycodone
Tuija H. Nieminen • Published 4 December 2010 •
Biology, Medicine, Chemistry

Oxycodone is an opioid used in the treatment of

moderate or severe pain. It is principally
metabolized in the liver by cytochrome P450 3A
(CYP3A) enzymes whereas approximately 10% is
metabolized by CYP2D6. Little is known about the
interactions between oxycodone and other drugs,
herbals and nutritional substances. In this work
the effects of CYP3A inducers rifampicin and St.
John’s wort and CYP3A inhibitors voriconazole,
grapefruit juice, ritonavir and lopinavir/ritonavir
were investigated on the pharmacokinetics and
pharmacodynamics of oxycodone. All studies
were randomized, balanced, placebo-controlled
crossover clinical studies in healthy volunteers.
The plasma concentrations of oxycodone and its
metabolites were determined for 48 hours and
pharmacodynamic parameters were recorded for
12 hours in each study. Pharmacokinetic
parameters were calculated by
noncompartmental methods. Rifampicin
decreased the plasma concentrations, analgesic
effects, and oral bioavailability of oral oxycodone.
St. John’s wort reduced the concentrations of
oxycodone and diminished the self-reported drug
effect. Voriconazole increased the exposure to
oral oxycodone by 3.6-fold whereas grapefruit
juice, which inhibits predominantly the intestinal
CYP3A, elevated the mean concentrations of
oxycodone by 1.7-fold. Ritonavir and lopinavir/
ritonavir increased the mean AUC of oxycodone
by 3.0and 2.6-fold, respectively, and prolonged its
elimination half-life. In spite of increased
oxycodone plasma concentrations during
concomitant administration of CYP3A inhibitors,
the analgesic effects were not increased. These
studies show that the induction or inhibition of
CYP3A alters the pharmacokinetics and
pharmacologic effects of oxycodone. The
exposure to oxycodone decreased after induction
and increased after inhibition of CYP3A. As a
conclusion, the clinicians should avoid
concomitant administration of CYP3A inducers or
inhibitors and oral oxycodone. If this is not
possible, they should be prepared to interactions
leading to impaired analgesia after CYP3A
inducers or increased adverse effects after
CYP3A inhibitors and oral oxycodone. Collapse

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Figures and Tables from this paper

Table 1

c-and
3-noroxycodol

NOROXYCODONE

СУР344
N-demethylation CYP2D6

24сн,н
,со
OXYMORPHONE
OXYCODONE NOROXYMORPHONE
g-and3-oxycodol
CYP206
O-demethylation' CYP206
СУРЗА4

g-and3-oxymorphi

Figure 1

Figure 2

Table 2

Figure 3

Table 3

Haem

Figure 4

Table 4

Figure 5

Table 5

Figure 6

Table 6

Figure 7

Phenotype Genotype Study

EM CYP2D6*1^*] 1/5,Il/6,III/S,IV/6,V/4
EM CYP2D6*1/*3
EM CYP2D6*1*4 1/4,11/4,I1/3,IV/3,V/3
EM CYP2D6*1%5
EM I/1,IV/1
EM CYP2D6*1/*9 1/1
EM CYP2D6*1^*10
EM CYP2D6*1^*4!
PM СУР2D6*3^*4
PM СУР2D6*4^4
IM CYP2D6*4^41
IM CYP2D6*10/*41
CYP2D6*1^*1×2
N=thenumberofthegenotypeappearingamong55volunteers;
EM=extensive,PM=poor,IM=intermediateandUM=ultrarapidmetabolizerviaCYP2D6
Romannumeral/Arabicnumeral=studynumber/thetotalnumbereachgenotypeinthe
correspondinestudy

Table 7

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Figure 10

Figure 11

Figure 12

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Figure 14

Figure 15

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