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THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
JPET 281:330 –336, 1997
Vol. 281, No. 1
Printed in U.S.A.
Pharmacogenetic Determinants of Codeine Induction by
Rifampin: The Impact on Codeine’s Respiratory, Psychomotor
and Miotic Effects1
YOSEPH CARACO2,3, JAMES SHELLER and ALASTAIR J. J. WOOD
Division of Clinical Pharmacology (Y.C., A.J.J.W.) and Pulmonary Department (J.S.), Vanderbilt University School of Medicine, Nashville,
Tennessee
Accepted for publication December 13, 1996
Codeine is a commonly used opioid that exerts its therapeutic effects through the formation of MOR (Snafilippo,
1948). The O-demethylation of codeine to MOR, which accounts for less than 10% of codeine biotransformation, has
been shown to cosegregate with CYP2D6 activity (Yue et al.,
1989; Mortimer et al., 1990; Yue et al., 1991). Among Caucasian populations, CYP2D6 is polymorphically distributed,
about 5% to 10% of individuals being of the PM phenotype
(Alvan et al., 1990; Wedlund et al., 1984). Those PMs who
lack functional CYP2D6 generate negligible amounts of MOR
from codeine, so codeine’s analgesic effect is markedly diminished (Yue et al., 1989; Sindrup et al., 1991; Desmeules et al.,
Received for publication July 22, 1996.
1
This study was supported by USPPH Grants GM 31304, GM 46622 and
RR 00095.
2
Merck International Fellow in Clinical Pharmacology.
3
Current Address: Yoseph Caraco, M.D., Division of Medicine, Clinical
Pharmacology Unit, Hadassah University Hospital, Jerusalem 91120, Israel
duced to a greater extent, resulting in a marked reduction in the
plasma concentrations of codeine and codeine metabolites and
elevated plasma concentrations of norcodeine, norcodeineglucuronide, and normorphine. The reduction in morphine
plasma concentration was associated in the EMs with a significant attenuation of codeine’s respiratory and psychomotor
effects, whereas its miotic effect was unaltered. In PMs, codeine’s respiratory and psychomotor effects were unaltered by
rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by
rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced
codeine N-demethylation more than codeine O-demethylation,
morphine plasma concentrations were reduced—and hence
codeine’s pharmacodynamic effects were attenuated—in EMs
of debrisoquin.
1991). Furthermore, we have recently shown that after codeine administration, the inability of PMs to produce MOR is
associated with significantly reduced respiratory, pupillary
and psychomotor effects of codeine (Caraco et al., 1996a).
The importance of CYP2D6 in mediating the biotransformation of many drugs, including antiarrhythmics (propafenone,
encainide and flecainide), antihypertensives (propranolol, metoprolol, timolol and debrisoquin), tricyclic antidepressants (desipramine, amitryptyline, nortryptyline and imipramine) and
opioids [codeine, ethylmorphine (O-deethylation), dextromethorphan and hydrocodone], is well established (Wrighton and
Stevens, 1992; Guengerich, 1994). In PMs of debrisoquin, the
metabolism of CYP2D6 substrates is substantially slower than
in EMs of debrisoquin, and for those drugs with a narrow
therapeutic window, this slow metabolism results in an exaggerated and potentially toxic pharmacological response (Eichelbaum and Gross, 1990; Tucker, 1994).
ABBREVIATIONS: EM, extensive metabolizer; PM, poor metabolizer; d, day; DMR, debrisoquin metabolic ratio; M3G, morphine-3-glucuronide;
M6G, morphine-6-glucuronide; NCG, norcodeine-glucuronide; C6G, codeine-6-glucuronide; NC, norcodeine; NM, normorphine; MOR, morphine;
VE55, minute ventilation at end-tidal CO2 55 mm Hg; DSST, digit symbol substitution test; AUC, area under the concentration-time curve; b,
elimination rate constant; CLo, oral clearance; T ⁄ , elimination half-life; AUE, area under the effect curve; ANOVA, analysis of variance; CYP2D6,
debrisoquin hydroxylase.
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ABSTRACT
Our objective was to examine the effect of rifampin on codeine’s pharmacodynamics and pharmacokinetics in extensive
(EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen
healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin,
received codeine (120 mg) before and after rifampin (600 mg/d)
for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. The pharmacokinetics of codeine were determined from the respective
plasma and urine concentrations. Before the administration of
rifampin, the pharmacodynamic effects of codeine were more
prominent in the EMs (P , .01). Rifampin significantly enhanced
codeine oral clearance by increasing its metabolic clearances
through N-demethylation and glucuronidation in both phenotypes, but its O-demethylation was induced only in EMs. Relative to base-line values, codeine N-demethylation was in-
1997
Codeine-Rifampin Interaction
Methods
Subjects. Sixteen healthy, nonsmoking Caucasian males, 10 EMs
and 6 PMs of debrisoquin, participated in the study. None of the
subjects was consuming any medication regularly, and the subjects
were requested not to use any medications, including alcohol and
over-the-counter medications, for the week before the initiation of
the study and throughout the entire study period. Mean (6 S.E.M.)
weight of the EM subjects was 78.7 6 2.1 kg, and their mean age was
32.1 6 1.1 years. Mean weight (87.3 6 5.5 kg) and age (34.2 6 1.3
years) values in the PM group were similar (P . .2), and each
subject’s weight in both groups was within 20% of his ideal body
weight. All subjects had a normal physical examination and underwent routine laboratory tests, including tests of liver and renal
function. The study protocol was approved by the Vanderbilt University Hospital Committee for the Protection of Human Studies,
and all the subjects gave written informed consent to participate in
the study.
The subjects were recruited from a list of potential volunteers who
had previously been phenotyped for both debrisoquin and mephenytoin hydroxylation capacity (Brosen, 1990; Wilkinson et al., 1989).
They also participated in another study of codeine’s effects (Caraco et
al., 1996a). Phenotypic assignment was reconfirmed, within 2 weeks
before the first study day, by the administration at bedtime of 10 mg
of debrisoquin (Declinax, Roche Laboratories, Nutley, NJ) together
with 200 ml of water. CYP2D6 activity was determined from the
DMR (i.e., the urinary ratio of debrisoquin and 49-hydroxydebrisoquin); a value above 12.6 in an 8-h urine collection was taken to
denote a PM phenotype (Brosen, 1990). Mean DMR value was 1.04 6
0.26 (range: 0.46–2.05) in the EMs and 93.6 6 21.5 (range: 21.4–151.2)
in the PMs.
Study design. The subjects received 600 mg of rifampin daily as
a single morning dose for 3 weeks. Codeine pharmacokinetics and
pharmacodynamics were evaluated within a week before the first
rifampin dose and again 1 h after the last rifampin dose. On the
morning of each study day and after an overnight fast and 24 h of
abstention from caffeine-containing food and beverages, the subjects
received a single 120-mg p.o. dose of codeine phosphate. Food was not
permitted for the initial 6 h, and then standardized, caffeine-free
meals were provided 6 and 10 h after drug intake. The subjects
remained in the study room for the entire 12 h of each study day. In
between study sessions the subjects could either sit or lie down, but
physical activity of any kind was not permitted. Blood (5 ml) was
sampled just before drug administration, every 10 min during the
first hour and 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 h after codeine
intake. Blood samples were obtained through an indwelling i.v. catheter, except for the last (24-h) blood sample, which was drawn
through a separate venipuncture. Plasma was immediately separated and kept frozen at 220°C until analyzed. Urine was collected
after drug intake over three time intervals: 0 to 12 h, 12 to 24 h, and
24 to 48 h. The subjects were closely monitored as inpatients for the
appearance of adverse effects for the initial 24 h after each codeine
dose and on a daily basis throughout the entire study period. The
consumption of rifampin was confirmed by frequent direct inquiries
and pill counting done at random on several occasions.
Codeine and codeine metabolites HPLC assay. The plasma
and urine concentrations of codeine and its metabolites were determined by an ion-paired reverse-phase HPLC method as published
previously with some modifications (Yue et al., 1991; Caraco et al.,
1996a). This method involved solid-phase extraction (Sep-pak C18,
Waters, Milford, MA) and the combined use of an UV detector (Spectroflow 773 UV detector, Kratos Analytical Instruments, Foster City,
CA) for the determination of M3G, NCG, C6G, NC and codeine and
a coulometric electrochemical detector (Coulochem 5100A with 5021
conditioning cell and 5011 analytical cell, ESA, Inc., Bradford, MA)
for the determination of M6G, NM and MOR. Preliminary testing
done in our laboratory indicated that neither rifampin nor rifampin
metabolites interfered significantly with the determination of codeine and codeine metabolites in plasma or urine. The chromatographic apparatus consisted of a 6000-A pump, two 730 data modules, a Wisp 710A autoinjector, and a mBondopak C18, 10-mm,
30033, 9-mm column (Waters Associates). The mobile phase consisted of 21% acetonitrile and 79% buffer containing 5 mM sodium
phosphate monobasic and 0.25 mM dodecyl sodium sulfate (pH 3.14).
Pharmacodynamic Evaluation
The effect on respiration, pupillary diameter and psychomotor
performance was assessed on each study day 0.5, 1, 1.5, 2, 3, 4, 5 and
6 h after the intake of codeine. Three pharmacodynamic measurements were performed before the administration of codeine, and the
average was taken as the base-line value for that particular day.
Measuring the effect on respiration. The effect on respiration
was evaluated by measuring resting minute ventilation, the endtidal carbon dioxide content, and the ventilatory response to increasing concentrations of CO2 by using the rebreathing method of Read
(1967). In brief, the subjects were requested to breathe through a
mouthpiece while wearing a nose clip until the minute ventilation
and the end-tidal CO2 were stable. Then they were connected
through a three-way valve to a balloon containing 1.5 times their
respective vital capacity volume of a gas mixture of 7% carbon
dioxide and 93% oxygen. The increasing concentration of carbon
dioxide stimulated a progressive hyperventilation that was continued for approximately 2 min, by which time the end-tidal CO2 had
reached a value of approximately 60 mm Hg. Tidal volume, ventilatory rate and end-tidal CO2 were continuously measured by a computerized exercise module (Cybermedics, Boulder, CO), using a
pneumotach and infrared CO2 analyzer. The instrument was calibrated before the determination of each CO2-response curve. To
familiarize the subjects with the procedure, the participants underwent a single rebreathing session a week before the study began and
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CYP2D6 activity is largely genetically determined (Bock et
al., 1994; Steiner et al., 1985). The influence of various factors such as liver disease, age, gender and diet on the in vivo
indexes of CYP2D6 is generally of minor magnitude compared with the major genetic effect (Bock et al., 1994; Steiner
et al., 1985; Larrey et al., 1989). On the other hand, subtherapetic doses of quinidine, a non-CYP2D6 substrate, produce
complete inhibition of the enzyme in EMs, resulting in a
process termed phenocopying (Nielsen et al., 1990). Conversely, enzyme induction by cigarette smoking, the consumption of oral contraceptives or the administration of a
potent cytochrome P450 inducer such as phenobarbital do
not affect the in vivo indexes of CYP2D6 (Bock et al., 1994;
Eichelbaum et al., 1986; Schellens et al., 1989). The effect of
rifampin on reactions mediated by CYP2D6 is less clear. In
EMs of debrisoquin, rifampin administration was associated
with a 30% increase in the metabolic clearance of sparteine,
but the debrisoquin metabolic ratio was not affected (Eichelbaum et al., 1986; Leclercq et al., 1989). In PMs of debrisoquin, a 6-fold increase in the metabolic clearance of sparteine
and a significant decrease in the debrisoquin metabolic ratio
were noted after the administration of rifampin, but the
phenotypic assignment changed from PM to EM in only 2 out
of the 6 genotypic PMs (Eichelbaum et al., 1986; Leclercq et
al., 1989).
If enzyme induction alters codeine O-demethylation to
MOR, this would be expected to produce profound changes in
codeine’s pharmacodynamic effects. The present study was
therefore undertaken to determine the effect of rifampin on
the pharmacokinetics and pharmacodynamics of codeine in
EMs and PMs of debrisoquin.
331
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Caraco et al.
12
12
AUC03`. Codeine partial metabolic clearances by glucuronidation
(CLglucuronidation), N-demethylation (CLN-demethylation) and O-demethylation (CLO-demethylation) were calculated as follows:
CLglucuronidation 5 CLO z UC6G / dose
CLN-demethylation 5 CLO z (UNC 1 UNCG 1 UNM) / dose
CLO-demethylation 5 CLO z (UM 1 UM3G 1 UM6G 1 UNM) / dose
U represents the urinary molar amount of the respective codeine
metabolite. Renal clearance (renal CL) was determined by dividing
the urinary molar amount of codeine or one of its metabolites by the
respective AUC03`.
Pharmacodynamic measurements were converted to percent of
base line, and the AUE over the initial 6 h after drug administration
(AUE036) was calculated by the trapezoidal rule.
Inter- and intraphenotypic comparisons were carried out by twoway ANOVA with repeated measurements, followed if appropriate
by paired or unpaired Student’s t test or nonparametric test (Wilcoxon signed rank test), as indicated. Linear and Spearman correlation tests were used to evaluate the relationship between pharmacokinetic and pharmacodynamic variables. P values of less than .05
were considered statistically significant.
Results
The data obtained on the study day before the administration of rifampin have been published previously (Caraco et
al., 1996a). One of the EM subjects, who experienced marked
drowsiness and nausea after the first codeine dose, decided
not to participate in the second study day, so data for only 9
EMs were available for analysis.
Pharmacokinetics: before rifampin. Morphine and
morphine metabolites were present only in the plasma samples obtained from EM subjects. Overall, codeine CLo and its
partial metabolic clearances through glucuronidation and
N-demethylation did not differ between EMs and PMs, but
the partial metabolic clearance by O-demethylation was
about 200-fold greater in the EM than the PM subjects
(162.7 6 36.6 vs. 0.86 6 0.65 ml/min respectively, P , .002)
(fig. 1).
Fig. 1. Mean (6 S.E.M.) codeine CLo and
the partial metabolic clearances by glucuronidation,
O-demethylation
and
N-demethylation before (EMs ■, PMs h)
and after rifampin (v). (Codeine CLo, codeine oral clearance; CLGlucuronidation,
partial metabolic clearance by glucuronidation; CLO-demethylation, partial metabolic clearance by O-demethylation;
CLN-demethylation, partial metabolic
clearance by N-demethylation)
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as part of the screening process to simulate the test conditions
during future study days.
The data obtained in each study session were analyzed by plotting
the minute ventilation measured at 10-s intervals against the respective end-tidal CO2 tension. The slope of the line relating minute
ventilation to CO2 tension (the slope of the CO2-response curve) and
the VE55 were calculated by least-squares linear regression analysis.
Measuring the effect on pupillary diameter. A 35-mm camera
(Nikon FG) equipped with a 53-mm micro-Nikon lens and a ringflash (Nikon 5B-21B) and attached to a chin-head rest was used to
photograph periodically the subject’s left eye from a fixed distance.
Light conditions were monitored by a light meter (Minolta autometer
2) and were kept constant throughout the entire study period. The
pupil and iris diameters in their longest axis were measured from a
5-by-7-inch color print with the aid of a ruler and a caliper. To avoid
measurement errors that might have occurred by slight change in
the location of the eye relative to the camera lens, the ratio of pupil
diameter to iris diameter was used for pharmacodynamic evaluation.
The coefficient of variation for repeated calculations of the ratio of
pupil diameter to iris diameter from duplicates of the same print was
2.5%.
Measuring the effect on psychomotor performance. Psychomotor performance was evaluated through the subjects’ periodic
performance of a revised DSST (Wechsler, 1981). The subjects were
given 90 s to fill in, with the appropriate letters, as many empty
boxes as they could according to a figure-letter code provided on the
top of each form. The number of boxes that were correctly filled in
within the time limit of 90 s was taken as the score. In order to
minimize the effect of learning on the DSST results, the subjects did
the test twice a week before the first study day, and several different
test versions were used at different times throughout the study days.
Data analysis. Plasma concentrations of codeine and its metabolites were plotted semilogarithmically against time, and the respective (b) were derived by least-squares linear regression analysis of
the terminal portions of the curves. Codeine and codeine metabolite
AUCs until the last measured concentration (AUC03t) were calculated by the log-trapezoidal rule and extrapolated to infinity
(AUC03`). The T ⁄ of codeine and its metabolites was calculated from
T ⁄ 5 0.693/b. Codeine was assumed to be completely absorbed from
the GI tract (Bechtel and Sinterhauf, 1978), so 120 mg of codeine
phosphate corresponded to 103 mg of codeine base. Codeine CLo was
derived from the ratio between the codeine dose and codeine
Vol. 281
1997
Codeine-Rifampin Interaction
TABLE 1
Mean (6 S.E.M.) codeine and codeine metabolites
pharmacokinetics before and after the administration of rifampin
in EMs
T ⁄ (h)
AUC03` (nMzh)
12
Compound
M3G
M6G
NM
MOR
NC
NCG
C6G
COD
a
b
c
Before
After
Before
3.68
(0.60)
4.17
(0.97)
9.24
(1.02)
3.24
(0.60)
3.34
(0.63)
5.24
(0.44)
2.87
(0.28)
2.55
(0.22)
2.14
(0.28)
2.04
(0.37a)
4.66
(0.39c)
1.27
(0.33a)
2.71
(0.25)
3.52
(0.28c)
2.25
(0.12a)
2.38
(0.16)
1461
(210)
401
(89)
606
(84)
62.0
(12.2)
500
(50)
2164
(243)
38853
(1959)
3160
(286)
P , .05
P , .01
P , .001
After
849
(117b)
155.9
(31.7a)
1515
(165c)
23.4
(6.0a)
1149
(167b)
3638
(467a)
27816
(1612c)
644
(98c)
Renal Clearance
(ml/min)
Before
After
223.0
(52.5)
174.2
(31.1)
244.0
(47.0)
96.0
(18.1)
328.3
(67.1)
86.6
(28.8)
79.5
(9.3)
86.6
(17.7)
233.6
(48.3)
192.8
(24.2)
243.1
(25.2)
51.0
(25.9)
324.5
(63.5)
134.9
(26.1)
102.3
(11.1)
66.3
(18.7)
TABLE 2
Mean (6 S.E.M.) codeine and codeine metabolites
pharmacokinetics before and after the administration of rifampin
in PMs
T ⁄ (h)
12
AUC03` (nMzh)
Renal Clearance
(ml/min)
Before
Before
After
213.2
(18.6)
103.5
(38.5)
87.2
(4.79)
51.8
(10.0)
246.6
(37.1)
123.8
(22.9)
86.0
(7.8)
35.5
(22.8)
Compound
Before
NC
NCG
C6G
COD
a
b
c
6.56
(1.50)
5.61
(1.07)
3.01
(0.18)
2.93
(0.23)
After
3.26
(0.42a)
4.49
(1.07a)
2.04
(0.24b)
1.47
(0.31c)
After
1388
1888
(327)
(372)
1534
3075
(192) (643a)
42516 26382
(4557) (2179b)
3072
578
(489) (155c)
P , .05
P , .01
P , .001
than the percent increase in codeine CLo (P , .004) and the
percent increase in codeine’s partial metabolic clearances
through glucuronidation (P , .004) and O-demethylation
(P , .01). In PMs, the percent induction of the N-demethylation pathway was significantly greater than the percent
induction of the glucuronidation (P , .05) and the O-demethylation (P , .001) pathways. The renal clearance of codeine and codeine metabolites was not affected by the treatment with rifampin in either phenotype.
Pharmacodynamics: before rifampin. The pharmacodynamic effects of codeine in these EMs and PMs of debrisoquin have been published previously (Caraco et al., 1996a).
Briefly, before rifampin treatment, the extent of codeine’s
respiratory, psychomotor and pupillary effects was significantly greater in the EMs than in the PMs, resulting in a
greater effect on resting minute ventilation (P , .01), resting
end-tidal CO2 (P , .01), VE55 (P , .01), slope of the CO2response curve (P , .003), psychomotor performance as evaluated by DSST (P , .008) and pupillary constriction (P ,
.007) (figs. 2 A and B).
Pharmacodynamics: after rifampin. In the EMs, the
treatment with rifampin significantly attenuated codeine’s
respiratory and psychomotor effects, resulting in a significantly lower effect on resting minute ventilation (P , .003),
resting end-tidal CO2 (P , .01), VE55 (P , .001), slope of the
CO2-response curve (P , .01) and psychomotor function as
evaluated by DSST (P , .001) (fig. 2A). In contrast, codeine’s
miotic effect was not significantly changed in EMs by the
treatment with rifampin (P . .2) (fig. 2A). In the PMs, the
only significant effect of rifampin treatment was to reduce
codeine’s pupillary effect (P , .001); its respiratory and psychomotor effects were unaltered (P . 0.3) (fig. 2B).
The attenuation of codeine’s respiratory and psychomotor
effect by rifampin was significantly greater in the EMs than
in the PMs, resulting in a greater decrease in codeine’s effect
on resting minute ventilation (P , .01), VE55 (P , .01), slope
of the CO2-response curve (P , .03) and psychomotor performance evaluated by DSST (P , .03) (fig. 3). Thus after the
administration of rifampin, no significant differences were
noted between EMs and PMs in codeine’s respiratory and
psychomotor effects (P , .3), but its miotic effect was still
greater in the EMs than in the PMs (P , .01).
When the subjects of both phenotypes were analyzed together, the decreases in codeine’s effects on resting minute
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b) Pharmacokinetics: after rifampin. The change in
codeine pharmacokinetics caused by rifampin is described as
mean (6 S.E.M.) percent change derived from the individual
difference between the rifampin and the codeine-alone study
days. After the administration of rifampin, codeine and C6G
plasma concentrations were significantly reduced in both
phenotypes, and the respective AUCs decreased by a mean of
79.4 6 2.3% and 28.1 6 3.4% in the EMs (P , .001) (table 1)
and by a mean of 83.5 6 3.0% (P , .001) and 36.6 6 4.5% (P ,
.003) in the PMs, respectively (table 2). In both phenotypes
the plasma concentrations of codeine’s N-demethylated metabolites were greater after rifampin, and accordingly the
AUCs of NC and NCG increased by 139 6 37% (P , .004) and
80 6 24% (P , .02) in the EMs and by 77 6 40% (P . .1) and
98 6 23% (P , .03) in the PMs, respectively (tables 1 and 2).
MOR and MOR metabolites were detected only in the
plasma samples obtained from EMs of debrisoquin. After the
administration of rifampin, the plasma concentrations of
M3G, M6G and MOR were lower, resulting in a mean decrease in the AUCs of 32 6 16% (P , .008), 53 6 9% (P , .03)
and 56 6 10% (P , .02), respectively. In contrast, after rifampin, NM plasma concentrations were higher and its AUC
was increased by a mean of 173 6 33% (P , .001) (table 2).
After the administration of rifampin, codeine CLo and its
partial metabolic clearances through glucuronidation and
N-demethylation were markedly enhanced by a mean of
489 6 130% (P , .001), 533 6 214% (P , .02) and 1937 6
845% (P , .002) in the EMs (fig. 1) and by a mean of 626 6
178% (P , .03), 297 6 88% (P , .02) and 1683 6 843% (P ,
.02) in the PMs, respectively (fig. 1). The partial metabolic
clearance through O-demethylation was increased in the
EMs only, by a mean of 826 6 311% (P , .002). In both EMs
and PMs, the absolute increase in codeine’s clearance
through glucuronidation was significantly greater than the
increase in its clearances through N- and O-demethylation
(P , .01). However, in the EMs, the percent increase in
codeine N-demethylation clearance was significantly greater
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Caraco et al.
Vol. 281
PM subjects reported mild nausea and drowsiness soon after
the administration of codeine, both before and after rifampin.
Discussion
ventilation, VE55, the slope of the CO2-response curve and
DSST were significantly correlated with codeine’s effects before rifampin (r 5 20.786, r 5 20.693, r 5 20.777 and r 5
20.775, respectively; P , .001). In addition, the debrisoquin
metabolic ratio was inversely and significantly correlated
with the decrease in codeine effect caused by rifampin (r 5
20.686 P , .001, r 5 20.839 P , .001, r 5 20.429 P , .05
and r 5 20.762 P , .001, respectively). In the EM subjects
only, codeine’s miotic effect after rifampin administration
was significantly correlated with MOR (r 5 20.706, P , .03)
and NM (r 5 20.747, P , .02) AUC values.
Adverse effects. After the administration of the first codeine dose, all EM subjects experienced dizziness, drowsiness and sleepiness. The peak effect was noted within 2 h,
and it usually subsided gradually within the initial 4 h after
codeine intake. Variable degrees of nausea were also reported by five of the EM subjects. After the administration of
rifampin, mild drowsiness and dizziness were experienced by
only five out of nine EMs, and this effect usually disappeared
within 2 h of the administration of codeine. Only 2 of the 6
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Fig. 2. Mean (6 S.E.M.) respiratory, psychomotor and pupillary area
under the % base-line effect curve (0 – 6 h) (AUE036) in the EM subjects
(A) and PM subjects (B) before (■) and after (v) the administration
rifampin. (AUE036, area under the percentage of base-line effect curve
at 0 to 6 h; CO2, resting end-tidal carbon dioxide concentration; CO2
Slope, the slope of the CO2-response curve; Pupil Ratio, the ratio of
pupil diameter to iris diameter.)
It is well established that enzyme induction by drugs such
as rifampin and phenobarbital alters drug metabolism. For
drugs whose effect is produced primarily by the parent compound, such induction would be expected to increase the
drug’s clearance, lower drug concentrations and decrease the
drug’s pharmacological effect (Fazio, 1991; Heimark et al.,
1987; Modry et al., 1985). However, for drugs such as codeine,
whose pharmacological effect is produced largely by its metabolism to the active metabolite, MOR, the effect of enzyme
induction on the drug’s pharmacodynamic effects depends on
the relative change in the plasma concentration of MOR.
Codeine is metabolized by a number of pathways, including
glucuronidation, O-demethylation to MOR and N-demethylation to NC (Yue et al., 1991). Because the plasma concentrations of morphine produced after enzyme induction depend on the relative extent of the induction of the various
pathways, including the further metabolism of MOR itself, it
was not possible to predict intuitively the net effect of rifampin induction on codeine’s pharmacodynamics before this
study. A further complicating factor is that the O-demethylation of codeine is mediated by CYP2D6, the cytochrome
P450 responsible for the metabolism of debrisoquin and
many other substrates (Yue et al., 1989; Wrighton and
Stevens, 1992; Guengerich, 1994). This cytochrome is polymorphically distributed so that PMs of debrisoquin who lack
active CYP2D6 might be expected to respond differently to
enzyme induction.
Previous studies have shown that exposure to enzyme inducers produces a selective induction of codeine metabolism
by different pathways. Cigarette smoking increased codeine
CLo by 17% but produced only a slight increase in codeine
glucuronidation. This resulted in no change in the formation
of MOR or in the codeine O-demethylation metabolic ratio
(Rogers et al., 1982; Hull et al., 1982). Subchronic treatment
with carbamazepine (400 – 600 mg/day for 3 weeks) resulted
in accelerated codeine N-demethylation, but as with smoking, the codeine O-demethylation ratio was unaltered (Yue et
al., 1994).
We have demonstrated in the present study that administration of rifampin to EMs of debrisoquin was associated with
a significant 2- to 12-fold increase in the partial metabolic
clearance of codeine through O-demethylation. The importance of considering the role played by other pathways of
codeine metabolism in defining the overall effect of enzyme
induction is shown by the fact that in spite of the enhanced
rate of codeine O-demethylation in EMs, MOR and MOR
glucuronides plasma concentrations were reduced overall
without any change in the codeine O-demethylation ratio.
The decrease in MOR plasma concentrations reflected the
relatively greater induction of the N-demethylation pathway
of codeine so that not only was the metabolism of codeine
itself shunted down that route to NC, but in addition, the
metabolism of MOR to NM was increased, further reducing
plasma morphine concentrations. The extent of enzyme induction by inducers such as rifampin is dose-dependent, 1200
mg/day having greater effect than 600 mg/day (Ohnhaus et
al., 1987; Price et al., 1986). In theory, it is possible that
1997
Codeine-Rifampin Interaction
335
Fig. 3. Mean (6 S.E.M.) decrease in the respiratory, psychomotor and pupillary effects of
codeine caused by the prior administration of
rifampin in EMs (■) and PMs (h). (CO2, resting
end-tidal carbon dioxide concentration; CO2
Slope, the slope of the CO2-response curve;
Pupil Ratio, the ratio of pupil diameter to iris
diameter.)
alter CYP2D6 activity slightly, increasing the metabolic
clearance of sparteine in EMs by 30% (Eichelbaum et al.,
1986) and decreasing the debrisoquin metabolic ratio in PMs,
resulting in the apparent phenotype being changed from PM
to EM in two of the genotypic PMs (Leclercq et al., 1989).
Rifampin treatment also increased 4-fold the metabolic clearance of propranolol by 4-hydroxylation, a CYP2D6-mediated
pathway. However, the absolute increase was much greater
in the EM than in the PM subjects, in whom the absolute
change was very small (Shaheen et al., 1989).
After the administration of rifampin, the respiratory and
psychomotor effects were greatly reduced in EMs, whereas
no significant change occurred in PMs. In vitro data have
shown that the affinity of codeine for m receptors is only
about 1/200 to 1/3000 that of its O-demethylated metabolite
MOR (Chen et al., 1991). Thus the marked differences previously noted between EMs and PMs of debrisoquin in codeine’s analgesic respiratory, psychomotor and miotic effects
has confirmed the central role played by the O-demethylated
metabolites in mediating codeine’s pharmacodynamic effects
(Sindrup et al., 1991; Caraco et al., 1996a). This was further
supported by our previous demonstration that the coadministration of quinidine with codeine that inhibits the production of MOR and its metabolites almost completely abolished
codeine’s respiratory, psychomotor and pupillary effects in
EMs of debrisoquin (Caraco et al., 1996a). The present study
provides the interesting additional finding that codeine’s effects are also decreased by an enzyme inducer, rifampin,
because of its ability to induce codeine N-demethylation preferentially, shunting metabolism down that pathway and decreasing the plasma concentrations of its active metabolites
MOR and M6G. Thus, through opposite mechanisms, quinidine and rifampin both significantly reduced MOR and M6G
plasma concentrations in EMs of debrisoquin, decreasing
markedly codeine’s pharmacodynamic effects.
The explanation for the persistence of the miotic effects of
codeine in EMs of debrisoquin, despite the lower MOR and M6G
plasma concentrations, is unclear. Like the respiratory and
analgesic effects, the pupillary constrictive effect of opioids is
mediated through m receptor stimulation (Mather, 1989). Nor-
Downloaded from jpet.aspetjournals.org at ASPET Journals on June 12, 2017
exposure to higher and to lower rifampin doses may have
different effects.
The percent increase in codeine N-demethylation was significantly greater in the present study than the percent increase in codeine’s O-demethylation and glucuronidation.
There appears to be a close link between the extent of induction and the nature of the biochemical reaction(s) involved in
the biotransformation of the drug in question. Thus when the
same inducer is administered concomitantly with different
drugs, the extent of induction may vary greatly (Venkatesan,
1992; Price et al., 1986; Baciewiez and Self, 1984). Furthermore, for a drug like antipyrine whose metabolism probably
involves several different P450s, the administration of rifampin has been shown to induce the formation of norantipyrine preferentially (Teunissen et al., 1984). The inducing
effect of rifampin appears to be most prominent for drugs
metabolized by CYP3A4. It is therefore of interest that by
using human hepatic microsomal preparations in vitro, we
have recently shown that CYP3A4 is the major enzyme involved in codeine N-demethylation (Caraco et al., 1996b).
Therefore, the marked increase in NC, NCG and NM and the
parallel reduction in MOR, NCGs and C6G plasma concentrations can be ascribed to the preferential induction of
CP3A4 by rifampin (Ged et al., 1989). In the PMs of debrisoquin, rifampin treatment resulted in enhanced codeine Ndemethylation and glucuronidation, but codeine O-demethylation was unaffected.
The activity of CYP2D6 is believed to be determined primarily by genetic factors, which accounts for as much as 79%
of the interindividual variability in debrisoquin 4-hydroxylation (Bock et al., 1994; Steiner et al., 1985; Eichelbaum et al.,
1986). Similarly, the inducibility of CYP2D6 by potent enzyme inducers is generally of minor magnitude. Debrisoquin
hydroxylase activity was not enhanced in liver microsomes
derived from rats treated with a variety of inducers, including phenobarbital, 3-methylcholanthrene, dexamethasone
and b-naphthoflavone (Wolff and Strecker, 1985; Birgersson
et al., 1985). Similarly, in humans phenobarbital does not
appear to alter sparteine metabolic clearance (Eichelbaum et
al., 1986; Schellens et al., 1989). However, rifampin does
336
Caraco et al.
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morphine binds to m receptors with approximately 1/4 the affinity of MOR (Chen et al., 1991) and is thought to exert about
25% of the analgesic effect of MOR in postsurgical patients
(Lasagna and DeKornfeld, 1958). Hence, it is possible that after
rifampin, codeine’s miotic effect was retained in EMs by the
2.7 6 0.3-fold mean increase in the NM AUC, which at least
partially counterbalanced the drop in MOR plasma concentrations. The finding that the NM AUC value after rifampin was
significantly correlated with codeine’s miotic effects, but not
with its respiratory or psychomotor effects, therefore provides
further support for this hypothesis.
Codeine demethylation to produce MOR is enhanced by treatment with rifampin in EMs, but not in PMs, of debrisoquin. The
preferential induction of codeine’s biotransformation by rifampin was associated with a greater percent increase in codeine’s N-demethylation than the percent increase in glucuronidation and O-demethylation. It therefore resulted in
decreased plasma concentrations of the main active metabolites, MOR and M6G. The reduced concentrations of the active
metabolites produced a significant attenuation of codeine’s respiratory and psychomotor effects in the EMs but not in the PMs.
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