Pharmacokinetics and pharmacodynamics

of codeine in end-stage renal disease

The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide,
morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose
of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers
and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were
determined by sensitive and specific R1A procedures. Pharmacodynamics were assessed by pupillometry
and vital sign determinations. Codeine elimination half-life and mean residence time were increased
significantly in the hemodialysis group (18.69 ± 9.03 hours and 12.77 ± 7.09 hours, mean ± SD,
respectively) compared with the healthy volunteer group (4.04 ± 0.60 hours and 3.90 ± 0.52 hours,
respectively). The total body clearance and volume ofdistribution ofcodeine were not significantly different
between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites
were also not significantly different between the groups, in part as a result of significant interpatient
variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal
clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen
may be required in some patients with uremia receiving multiple-dose codeine therapy. (CLIN PHARMACOL
TITER 1988;43:63-71.)

David R. P. Guay, Pharm.D., Walid M. Awni, Ph.D., John W. A. Findlay, Ph.D.,

Charles E. Halstenson, Pharm.D., Paul A. Abraham, M.D., John A. Opsahl, M.D.,
Evelyn C. Jones, B.S., and Gary R. Matzke, Pharm.D.
Minneapolis, Minn., and Research Triangle Park, N.C.

Although codeine, alone or in combination with acet-
aminophen or acetylsalicylic acid, has been widely used
as an analgesic for many years, there are only limited
data on the pharmacokinetics of this compound in
humans."' Specifically, the pharmacokinetics and
pharmacodynamics of codeine have not been evaluated
prospectively in patients with renal failure. The phar-
macokinetics and pharmacodynamics of meperidine,
propoxyphene, dihydrocodeine, and morphine are sig-
nificantly altered in the presence of renal disease." 16
From the Drug Evaluation Unit, Hennepin County Medical Center,
and the College of Pharmacy and School of Medicine, University
of Minnesota, Minneapolis, and Wellcome Research Laboratories,
Department of Medicinal Biochemistry, Research Triangle Park.
Presented in part at the Sixteenth Annual Meeting of the National
Kidney Foundation, Washington, D.C., December 1986, and the
Eighty-eighth Annual Meeting of the American Society for Clinical
Pharmacology and Therapeutics, Orlando, Fla., March 25-28,
1987.
Received for publication March 17, 1987; accepted July 19, 1987.
Reprint requests: David R. P. Guay, Pharm.D., Drug Evaluation
Unit, Division of Nephrology, Department of Medicine, Hennepin
County Medical Center, 701 Park Ave., Minneapolis, MN 55415.
Furthermore, two recent reports suggest that patients
with renal failure may develop severe codeine-induced
narcosis while receiving standard doses. 7.'8 Altered
pharmacokinetics secondary to renal insufficiency or
enhanced sensitivity to codeine could account for the
observed effects.
This study was designed to rigorously investigate the
pharmacokinetics and pharmacodynamics of codeine
and its three major metabolites, codeine glucuronide,
morphine, and morphine glucuronide, after intravenous
and oral administration of single doses of codeine to
normal volunteers and patients on chronic hemodi-
alysis.
MATERIAL AND METHODS
Subjects. Six healthy subjects (creatinine clearance
>90 ml/min) and six patients with end-stage renal dis-
ease undergoing hemodialysis therapy participated in
this study. Mean ( ± SD) age, body weight, and height
in the normal volunteer group were 27.8 ± 3.7 years,
73.1 ± 11.6 kg, and 174.0 ± 7.3 cm, respectively.
Mean age, body weight, and height in the group
on chronic hemodialysis were 45.5 ± 18.9 years,

63

64 Guay et al.
10001
1111
2 4 6 8 10 12 14 16 18
Time (hr)
Fig. 1. Mean ( SD) plasma codeine concentrations after
intravenous administration of 60 mg codeine phosphate in six
healthy volunteers ()
and six patients on hemodialysis (0).
81.5 ± 23.2 kg, and 168.3 ± 13.0 cm, respectively.
The sex distribution (male female) in the healthy vol-
: monitored immediately before and 0.5, 1, 2, 3, 4, 5,
unteer group and group on chronic hemodialysis was
4:2 and 3:3, respectively. The only significant differ-
ence between the groups in demographic parameters
was the difference in age. All subjects underwent a
medical history, physical examination, and laboratory
assessment before participation in the study. The vol-
unteers were considered healthy if all physical findings
and laboratory assessments were within the normal
range. Subjects were excluded if they had received any
narcotic analgesics within 2 weeks of the study or if
they had known or suspected "true hypersensitivity" to
codeine. All subjects gave written, informed consent
to participate in the study, which had been approved
by the Research Advisory Committee of Hennepin
County Medical Center.
Study design. Each subject received codeine on two
occasions. On one occasion a single 60 mg oral dose
of codeine sulfate (Eli Lilly and Co., Indianapolis, Ind.,
lot 0002-2555-02, equivalent to 51.6 mg codeine base)
was administered with 240 ml water. On the other oc-
casion a single 60 mg intravenous dose of codeine
phosphate (Winthrop-Breon, New York, N.Y., lot
M113AH, equivalent to 45.2 mg codeine base) was
administered over 15 minutes with an infusion pump
GUN PHARMACOL THER
JANUARY 1988
(Sage Instruments, Cambridge, Mass.). The order of
drug administration was randomly allocated.
Oral and intravenous doses were administered after
an 8-hour overnight fast, and food or beverages other
than water were not allowed until at least 2 hours after
drug administration. Study phases were separated by at
least a 1-week washout period. All studies on patients
receiving hemodialysis were performed on off-dialysis
days.
Seven milliliter blood samples were collected into
EDTA-containing Vacutainer tubes (Becton-Dickinson,
Rutherford, N.J.) with a heparin lock before drug ad-
ministration and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4,
6, 8, 10, and 12 hours after drug administration.
Blood samples were also obtained 24 hours after drug
administration by venipuncture. All blood samples
were centrifuged and the harvested plasma stored at
- 70° C until analysis. All urine produced during the
20 22 24
24-hour interval after drug administration was collected
(when possible, in the group on chronic hemodialysis)
in the following fractions: 0 to 2, 2 to 4, 4 to 6, 6 to
12, and 12 to 24 hours. Urine volumes were measured
-
and aliquots were stored at 70° C until analysis.
The following pharmacodynamic assessments were
evaluated after each administration of codeine: respi-
ratory rate, sitting blood pressure, heart rate, level of
consciousness, and pupillary reactivity to light were
7, 8, 9, 10, 11, 12, and 24 hours after drug admin-
istration. Pupillary diameter was determined before
drug administration and 2, 5, 7, and 10 hours after drug
administration by 35 mm photography using a fixed
focal-length lens and a scale affixed to the subject's
eyebrow.I9 The timing of pupillometry was dictated by
the frequent blood sampling times. Side effects such as
nausea, sedation, and constipation were documented
after subject interview.
Analytic methodology
Determination of free (unconjugated) morphine
and codeine in plasma. Unconjugated alkaloids in
plasma were measured by direct RIAs that employed
antisera raised to conjugates of codeine' and mor-
phine' coupled to carrier protein via the piperidine ring
of the respective alkaloids. This route of conjugation
results in antisera with very low cross-reactivities with
the major glucuronide metabolites.22 For example, the
cross-reactivity of codeine-6-glucuronide, morphine,
and morphine-6-glucuronide in the codeine assay
with the antisera used in this study (NC-4/11, Well-
come Research Laboratories, Research Triangle Park,
N.C.) was 0.14%, 0.63%, and 0.01%, respectively.
VOLUME 43
NUMBER I
Cross-reactivity with norcodeine was 20%. However,
cross-reactivity with N-demethylated metabolites is un-
important in view of the negligible circulating concen-
trations of these compounds in plasma. In addition,
using assays of extracted and unextracted samples, and
antisera with norcodeine cross-reactivity of 0.14%, no
interference with codeine determinations was noted (un-
published observation). The details of these assay pro-
cedures, including sensitivity, specificity, and reprod-
ucibility data, have been reported previously."'
Determination of total (conjugated plus unconju-
gated) morphine and codeine in plasma. Plasma
(0.2 ml) was mixed thoroughly with Glusulase (Du-
pont Pharmaceuticals, Wilmington, Del.; containing
191,789 U glucuronidase activity and 21,928 U sul-
fatase activity/ml; 50 Ill) and sodium acetate buffer (0.2
mol/L, pH 5.5; 0.2 ml), and the mixture was incubated
at 37° C for 20 hours. Individual plasma hydrolysates
were then diluted with assay buffer (phosphate-buffered
saline solution containing 0.1% gelatin) to bring them
into the range of the respective assay standard curves
before RIA analyses for morphine and codeine using
the antisera described above. Standard and control so-
lutions of codeine and morphine, respectively, were
also carried through the entire enzyme treatment and
assay procedure. Assay values were corrected to reflect
the efficiency of enzyme hydrolysis as indicated by the
recovery of codeine and morphine after hydrolysis of
standard concentrations of codeine-6-glucuronide and
morphine-3-glucuronide under the conditions described
above.
Determination of free morphine and codeine in
urine. Urine (0.5 ml) was mixed with 1 mol/L Na,CO,
(pH 9.5): glycerol (1:1; 0.5 ml) and extracted twice
with chloroform: ethanol (95:5; 2 m1). The combined
organic extracts were evaporated to dryness under a
stream of dry nitrogen and the residue was solubilized
by addition of ethanol (0.05 ml), mixing, and addition
of assay buffer (0.45 m1). These extracts were then
assayed as indicated above; standard and control so-
lutions of the alkaloids were again carried through the
entire procedure to allow for internal compensation for
losses.
Determination of total morphine and codeine in
urine. Urine (0.5 ml) was mixed thoroughly with 0.5
ml of a solution (5 mg/ml) of p-glucuronidase (Miles
Laboratories, Inc., Elkhart, Ind.; containing 2000 U
glucuronidase activity/mg) in 0.2 mol/L sodium ace-
tate buffer (pH 5.5) and the mixture was incubated at
37° C for 20 hours. Then 1 mol/L Na2CO3 (pH 9.5):
glycerol (1 :1; 0.5 ml) was added and the tube con-
tents were vortex mixed and extracted twice with
Codeine in renal failure 65
500
100
cr)
50
z
-NTT
10
0 5.0
1.0 111111111111
2 4 6 8 10 12 14 16 18 20 22 24
Time (hr)
Fig. 2. Mean ( -± SD) plasma codeine concentrations after oral
administration of 60 mg codeine sulfate in six healthy vol-
unteers ()
and six patients on hemodialysis ().
chloroform: ethanol (95:5; 2 m1). The extracts contain-
ing drug and metabolite were processed and analyzed
as described above for determination of free concen-
trations of codeine and morphine in urine, with the
exception that dried extracts were reconstituted in 0.1
ml ethanol and 0.9 ml assay buffer. Standard and con-
trol solutions of the alkaloids were carried through all
steps of the procedure to allow for internal compen-
sation for losses.
Data analysis?3'24 Pharmacokinetic parameters of
codeine, codeine glucuronide, morphine, and morphine
glucuronide were determined by model-independent
analysis. Maximum plasma concentrations (Cmax) and
time to attain Cma, (t,RR) were determined from the ob-
served plasma concentration-time data. The disposition
rate constants (k) for codeine were calculated from the
10-, 12-, and 24-hour data points on the terminal por-
tions of the semilogarithmic plasma concentration-time
curves by nonlinear regression analysis. Elimination
half-lives (t172) were obtained by dividing in 2 by k.
AUC was calculated for the 24 hours after administra-
tion (AUC(0_24)) by the linear trapezoidal rule and cal-
culated to infinity (AUC,) for codeine by the equa-
tion: AUC0c = AUC(0 24) ± C24/k, where C-)4 is the
codeine plasma concentration 24 hours after adminis-
tration. Total body (CL), renal (CL,), and nonrenal
(CL) clearances were calculated according to the
following equations: CL = dose/AUC,, CLR =
Aet,_12/AUCt,2, and CL, = CL CLR, where dose is
 CLAN PHARMACOL THER
66 Guay et al. JANUARY 1988

Table I. Model-independent pharmacokinetic parameters of codeine after intravenous administration to

healthy volunteers and patients on hemodialysis
t1/2 AUC0-> CL CLR CLNR MRT V AF
Subjects (nglml) (hr) (nglml hr) (mIlminIkg) (ml/mm/kg) (mIlminIkg) (hr) (LIkg) (%)

Healthy
volunteers
1 169 4.24 448 17.8 1.73 16.07 3.67 3.93 102
2 203 3.49 575 16.0 1.41 14.59 3.37 3.11 84
3 144 4.72 580 18.6 3.17 15.43 4.22 4.71 113
4 361 4.17 828 13.2 1.24 11.96 3.36 2.65 100
5 360 3.14 1167 9.3 0.92 8.38 4.08 2.28 75
6 130 4.47 757 15.3 1.80 13.50 4.67 4.28 107
Mean 228 4.04 726 15.0 1.71 13.32 3.90 3.49 97
± SD 106 0.60 256 3.4 0.78 2.83 0.52 0.96 15
Hemodialysis
patients
7 248 14.94 526 24.1 0.00 24.10 7.41 10.71 358
8 140 26.96 426 14.2 0.07 14.13 16.40 13.96 629
9 340 9.79 939 8.4 0.00 8.40 5.58 2.83 235
10 545 33.28 1900 4.9 0.00 4.90 24.83 7.23 800
11 144 13.76 835 11.3 0.01 11.29 9.32 6.33 330
12 660 14.15 3502 3.3 0.03 3.27 13.07 2.62 340
Mean 346 18.69 1355 11.0 0.02 11.02 12.77 7.28 449
± SD 215 9.03 1175 7.6 0.03 7.55 7.09 4.45 217
P value 0.477 0.004 0.429 0.146 0.004 0.262 0.004 0.146 0.004
MRT, mean residence time; AF, accumulation factor at steady state expressed as percentage of codeine concentrations after the first dose based on a hypothetical
regimen of 60 mg codeine phosphate administered intravenously every 6 hours.

the codeine dose administered intravenously expressed
as milligrams of codeine base, Aet,.t2 is the urinary ex-
cretion of compound over the urine collection interval
t1-t2, and AUCto, is the AUC during the urine collection
interval t142.
The codeine volume of distribution at steady state
(V) and mean residence time were calculated by
statistical moment theory.' Absolute codeine bioavail-
ability (F) was calculated from the ratio of the dose-
adjusted AUC0_,0, of codeine after oral and intravenous
administration." Accumulation of codeine at steady
state was estimated with the equation: AF = 1.44 -
ti,2/T, where T is the dosing interval."
Pharmacodynamic parameters were evaluated as per-
centage change from baseline (immediately before dose
measurement). Statistical analysis was performed with
x2 test with Yates correction for proportion data,
ANOVA for repeated measures for pharmacodynamic
data, Mann-Whitney U test for pharmacokinetic data,
and linear regression-correlation analysis to examine
the relationship of age to pharmacokinetic parameters.
Statistical significance was assumed when P < 0.05.
RESULTS
In general, single-dose codeine administration was
well tolerated. An extension of this study to include
multiple-dose codeine administration had to be termi-
nated prematurely because of severe adverse reactions
in the first two patients on hemodialysis (protracted
nausea and vomiting after three and five doses, re-
spectively, lasting up to 5 days after drug discontin-
uation). The plasma codeine concentration-time curves
for the two study groups after intravenous and oral
administration of codeine are illustrated in Figs. I
and 2, respectively. Plasma codeine concentrations
were higher at all sampling points in the patients on
hemodialysis compared with the healthy volunteers.
The t112, mean residence time, and AF were signifi-
cantly greater and the CLR was significantly lower after
intravenous and oral administration in the patients on
hemodialysis compared with the healthy volunteers
(Tables I and II). Although C,RR, AUC,,s, Vss, CL, and
were not significantly different in the patients on
hemodialysis compared with the healthy volunteers,
substantial interpatient variability may have overshad-
owed these differences. Similarly, the absolute bio-
availability of codeine did not significantly differ be-
tween the two groups.
The pharmacokinetic parameters of codeine glucuro-
nide, morphine, and morphine glucuronide after intra-
venous and oral codeine administration are depicted in
Tables III and IV, respectively. After intravenous co-
deine administration the hemodialysis group exhibited
significantly reduced CI-, for the three metabolites and
VOLUME 43
NUMBER I Codeine in renal failure 67

Table II. Model-independent pharmacokinetic parameters of codeine after oral administration to healthy
volunteers and patients on hemodialysis
b/2 AUC0- CLR MRT AF
Subjects (nglml) (hr) (hr) (nglml hr) (ml/mm/kg) (hr) (%)
Healthy
volunteers
1 149 0.5 4.92 372 1.49 3.71 72.7 118
2 93 0.75 3.98 615 1.93 3.95 93.8 96
3 237 0.75 5.57 626 1.19 5.72 94.6 134
4 273 0.5 4.89 1193 0.75 4.59 126.2 117
5 69 1.0 3.68 743 1.03 4.32 55.7 88
6 214 1.5 3.73 344 2.68 4.74 39.9 89
Mean 172.6 1.6 4.46 649 1.51 4.51 80.5 107
It SI) 81.9 1.7 0.78 308 0.70 0.71 30.9 19
liennodialysis
patients
7 103 0.5 17.70 728 0.00 15.61 121.2 425
8 149 0.5 14.59 418 0.04 10.87 86.1 350
9 136 0.5 8.96 992 0.00 7.71 92.6 215
10 364 0.75 12.23 1363 0.00 10.14 62.8 293
11 221 1.0 10.00 357 0.03 6.29 37.4 240
12 103 0.33 14.73 1668 0.06 13.48 41.7 354
Mean 179.3 1.3 13.03 921 0.02 10.68 73.6 313
If: SD 100.3 1.8 3.27 523 0.03 3.48 32.3 78
P value 0.538 0.206 0.004 0.339 0.004 0.004 0.529 0.004
MRT, mean residence time; AF, accumulation factor at steady state expressed as percentage of codeine concentrations after the first dose based on a hypothetical
regimen of 60 mg codeine sulfate orally every 6 hours.

prolonged tma for morphine compared with the healthy
volunteers. The Cmax and AUC,0-24) of the three metab-
olites in the hemodialysis group were not significantly
different from those of the healthy volunteers, again
possibly because of the substantial interpatient vari-
ability in the hemodialysis group. After oral codeine
administration the hemodialysis group exhibited sig-
nificantly reduced CL, for the three metabolites and
significantly elevated AUC(0 24) for codeine glucuronide
compared with the healthy volunteers. Again, nonsig-
nificant differences in Cm., L., and AUC(0-24) with the
other metabolites in the hemodialysis compared with
the healthy volunteer group were noted. No significant
correlations were noted between age and any pharma-
cokinetic parameter.
Although statistical differences were noted between
the two groups in a few isolated comparisons, as might
be expected during multiple comparison statistical test-
ing, overall there were no statistically or clinically sig-
nificant differences between the two groups in pupil
diameter changes, blood pressure, pulse rate, or respi-
ratory rate.
DISCUSSION
Studies of several narcotic analgesics have demon-
strated altered drug pharmacokinetics and pharmaco-
dynamics in patients with renal disease. Normeperi-
dine, an active but toxic metabolite of meperidine, may
accumulate in patients with renal disease and cause
central nervous system toxicity manifested as tremor
or myoclonus or generalized seizures." Propoxyphene
and its active metabolite norpropoxyphene accumulate
during multiple-dose administration in anephric pa-
tients. Propoxyphene accumulation is thought to be sec-
ondary to reduced presystemic extraction.' Dangerous
toxicity may ensue in patients with uremia receiving
propoxyphene because naloxone is ineffective in man-
aging the cardiac toxic ities of the parent drug and active
metabolite. Dihydrocodeine therapy has been associ-
ated with unexpectedly prolonged narcosis and in-
creased Cmax and AUC in patients with uremia. l'.14 In-
creased sensitivity to morphine and accumulation of the
potent active metabolite morphine-6-glucuronide have
been noted in patients with renal failure.15.' The phar-
macokinetics and pharmacodynamics of codeine in ure-
mia have not been studied, despite the use of this com-
pound for many years.
The results of this study indicate that the pharma-
cokinetics of codeine and two of its three major me-
tabolites may be significantly perturbed in patients on
chronic hemodialysis. The CLR of codeine and all three
metabolites were significantly reduced in the patients
 CLIN PHARMACOL THER
68 Guay et al. JANUARY 1988

Table III. Model-independent pharmacokinetic parameters of codeine glucuronide, morphine, and morphine
glucuronide after intravenous administration of codeine to healthy volunteers and patients on hemodialysis
Codeine glucuronide Morphine

AUC,, CLR t. AUC(0 24) CLR

Subjects (nglml) (hr) (nglml hr) (mIlminIkg) (nglml) (hr) (nglml hr) (mIlminIkg)

Healthy
volunteers
1 1374 0.167 5507 0.51 3.5 0.5 17 4.63
2 1464 0.33 7202 0.44 6.6 2.0 83 1.14
3 1335 0.167 6180 0.78 1.7 1.0 29 0.75
4 1821 1.5 10396 0.28 2.7 4.0 45 0.21
5 3528 4.0 58905 0.05 7.5 0.5 104 0.45
6 1092 0.167 4974 1.29 0.8 2.0 6 13.90
Mean 1769 1.1 15527 0.56 3.8 2.4 47 3.51
± SD 894 1.5 21337 0.43 2.7 1.7 39 5.34
Hemodialysis
patients
7 2749 3.0 36359 0.00 4.2 3.0 76 0.00
8 1275 0.167 4097 0.01 2.5 3.0 35 0.34
9 2526 6.0 37918 0.00 4.4 6.0 82 0.00
10 1371 2.0 11323 0.00 3.8 8.0 81 0.00
11 1464 0.167 8058 0.01 1.0 6.0 20 0.18
12 3817 10.0 72737 0.01 1.1 10.0 24 0.01
Mean 2200 3.6 28415 0.00 2.8 6.0 53 0.09
± SD 1011 3.8 26137 0.00 1.5 2.8 30 0.14
P value 0.477 0.244 0.262 0.004 0.686 0.010 0.640 0.006

Table IV. Model-independent pharmacokinetic parameters of codeine glucuronide, morphine, and morphine
glucuronide after oral administration of codeine to healthy volunteers and patients on hemodialysis
Codeine glucuronide Morphine

AUC, 24I CLR t, AUG(0 24) CLR

Subjects (nglml) (hr) (nglml hr) (mIlminIkg) (nglml) (hr) (nglml hr) (mIlminIkg)

Healthy
volunteers
1 1431 0.75 6364 0.61 10.4 0.75 119 0.83
2 1723 1.0 8982 0.55 9.2 1.0 104 0.85
3 1857 2.0 11973 0.27 2.9 3.0 47 0.22
4 3845 1.0 18079 0.21 7.1 1.5 91 0.19
5 1664 1.0 8500 0.39 18.3 1.0 146 0.45
6 1792 0.5 6519 0.69 10.6 0.5 104 1.09
Mean 2052 1.0 10070 0.45 9.8 1.3 102 0.61
± SD 890 0.5 4422 0.19 5.1 0.9 33 0.37
Hemodialysis
patients
7 5130 1.5 93166 0.00 10.7 1.0 181 0.00
8 1502 0.75 22313 0.00 7.9 2.0 116 0.02
9 3787 4.0 81862 0.00 7.8 6.0 152 0.00
10 6241 6.0 77287 0.00 7.6 2.0 133 0.00
11 1571 1.0 14790 0.00 5.0 0.6 105 0.02
12 2731 6.0 49562 0.01 1.0 24.0 20 0.01
Mean 3494 3.2 56497 0.00 6.7 5.9 118 0.01
±SD 1926 2.5 32791 0.00 3.3 9.1 55 0.01
P value 0.339 0.098 0.007 0.003 0.339 0.194 0.261 0.004
VOLUME 43
NUMBER I Codeine in renal failure 69

on hemodialysis compared with healthy volunteers. In

addition, tu, and mean residence time were significantly
greater in the group on hemodialysis compared with
Morphine glucuronide
the healthy volunteers. Despite substantial increases in
C t AUC0_24, CLR mean codeine AUCc after oral and intravenous ad-
(nglml) (hr) (nglml hr) (mIlminIkg) ministration (41.9% and 86.6%, respectively), Cma, at
the end of the intravenous infusion (51.8%), and V,
(108.6%) in the group on hemodialysis compared with
7.6 3.0 138 9.81 the healthy volunteers, these differences did not achieve
52.8 1.5 311 2.34 statistical significance. Similarly, despite the substantial
3.3 1.25 32 4.94 increases in mean codeine glucuronide AUCO34) after
13.7 3.0 151 0.71
24.8 24.0 459 1.09
intravenous administration (83.0%), morphine glucuro-
7.2 2.0 109 8.11 nide AUC(04) after oral and intravenous administration
18.2 5.8 200 4.50 (528.6% and 479.5%, respectively), and morphine
18.5 9.0 156 3.80 glucuronide Cma, after oral administration (172.4%),
these differences did not achieve statistical significance.
24.5 24.0 485 0.00 Substantial interpatient variability was apparent in the
19.2 2.0 299 0.22 group on hemodialysis. Marked interpatient pharma-
28.4 8.0 565 0.00 cokinetic heterogeneity of high hepatic clearance corn-
29.6 4.0 512 0.00 pounds has also been noted for labetalo125 and metha-
18..0
4.1
2
20.7
0.5
12
8.4
83
5012
1159
0.82
0.00
0.17
qualone.' Interindividual differences in hepatic cyto -
chrome P-450 concentrations and activities,' genetic
9.3 8.7 1896 0.33 factors,' and environmental factors such as diet, smok-
0.429 0.427 0.075 0.006 ing, medications, renal and other diseases, and expo-
sure to environmental chemicals (especially the hepatic
enzyme-inducing plasticizer di-2-ethylhexylphthalate
leached from hemodialysis tubing29-30) may have con-
tributed to the marked interindividual differences noted
in these patients.
Morphine glucuronide The prolongation in the t112 after oral and intravenous
administration in our patients on hemodialysis was sig-
C t AUCO24, CLR
nificant (Tables I and II) and suggests the potential for
(nglml) (hr) (ng/m1 hr) (mIlminIkg)
marked accumulation of codeine during multiple-dose
therapy. The estimated degree of accumulation of co-
deine at steady state in the patients on hemodialysis
19.3 3.0 201 8.61
during a hypothetical dosing regimen of codeine sulfate,
18.6 2.0 181 4.07
4.3 2.0 56 1.44 60 mg orally every 6 hours, was to values >300 percent
5.1 1.0 40 4.83 above those concentrations achieved after single-dose
89.4 1.5 556 1.09 administration. Four of the six patients on hemodialysis
28.4 2.0 326 3.56 would be expected to achieve toxic plasma codeine
27.5 1.9 227 3.94
concentrations (>500 ng/m13') at steady state. These
31.7 0.7 193 2.73
data are in striking contrast to the lack of accumulation
predicted in the healthy volunteers.
170.0 24.0 3675 0.00 The analytic methodology employed in this study
16.3 1.5 195 0.25 did not allow a differentiation between morphine-3-
173.0 24.0 3267 0.00
0.00
glucuronide and morphine-6-glucuronide. Thus the as-
53.9 2.0 853
21.1 1.5 268 0.23 sessment of the pharmacokinetics of morphine gluc-
15.1 12.0 305 0.00 uronide in this study represents a composite analysis.
74.9 10.8 1427 0.08 Additionally, the blood sampling scheme was not de-
76.2 11.0 1605 0.12 signed to characterize the elimination ti, of the
0.262 0.285 0.075 0.004
three metabolites, a necessary determinant for estimat-

70 Guay et al.
ing drug accumulation during multiple-dose adminis-
tration.
Data from the present study corroborate results of
previous studies documenting only minor alterations in
morphine pharmacokinetics in patients on chronic he-
modialysis when morphine-specific assay procedures
are employed."-"
Although alterations were noted in codeine and me-
tabolite pharmacokinetics in the patients on chronic he-
modialysis compared with the healthy volunteers, no
clinically relevant alterations in pharmacodynamics
were observed. This may have been in part a function
of the insensitivity of the dynamic assessments used,
the single-dose design of the study, or confounding
variables such as concomitant drug therapy, underlying
diseases, and fluctuating fluid status. In addition, the
effect of renal failure on the analgesic effect of codeine,
which may be the most relevant pharmacodynamic mea-
sure, was not assessed.
In conclusion, dosage modification of codeine with
a reduced maintenance dose or prolonged maintenance
dosing interval may be necessary in patients on chronic
hemodialysis to minimize toxicity and maximize effi-
cacy when multiple-dose therapy is anticipated. Further
studies with additional patients, control of confounding
variables, more sensitive dynamic assessments, and
multiple dosing will be required to confirm this rec-
ommendation.
We gratefully acknowledge the assistance of the nursing
personnel of the Clinical Research Unit and the artistic as-
sistance of D. Erickson.
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