and metabolism of codeine in man. A. Somogyi 1'2, ... and CLa (ml. rain -1) for codeine were 2.2, 0.81, and 252 ... In man codeine is principally metabo- lized by ...
Eur J Clin Pharmacol (1991) 41:379-382
© Springer-Verlag 1991
Short communications
Lack of effect of paracetamol on the pharmacokinetics and metabolism of codeine in man A. Somogyi 1'2, E Boehner 1,2, and Z. R. Chen 1 1 Department of Clinical Pharmacology, Royal Adelaide Hospital, North Terrace and 2 Department of Clinical and Experimental Pharmacology University of Adelaide, Adelaide, Australia
Received: October 2, 1990/Accepted in revised form: January 22, 1991
Summary. Plasma and urine concentrations of codeine and its measurable metabolites were determined by H P L C in six healthy subjects after a single 30 mg oral dose of codeine either alone or after 7 doses of i g paracetamol 8 hourly. After codeine alone, the tl/2 (h), A U C (gmol.1 1.h) and CLa (ml. rain -1) for codeine were 2.2, 0.81, and 252 respectively. These were not significantly altered by paracetamol: 2.2, 0.84, and 291 respectively. For codeine-6-glucuronide the values were 2.4, 22.0, and 29.7 respectively. These were not significantly different from those after codeine plus paracetamol: 2.4, 21.9, and 39.6. There were no significant differences between the two treatments in the apparent partial clearances (ml. min- 1) of codeine to morphine (88 codeine alone, 70 codeine plus paracetamol), to norcodeine (71 codeine alone, 88 codeine plus paracetamol), and to codeine-6glucoronide (820 codeine alone, 1022 codeine plus paracetamol). The urinary excretion of codeine-6-glucuronide, morphine, norcodeine, and codeine were not significantly different between the two treatments. Key words: Codeine; paracetamol, codeine-6-glucuronide, pharmacokinetics, metabolism, partial clearance, drug interaction
Codeine is frequently prescribed in combination with paracetamol (acetaminophen) for the treatment of mild to moderate pain. In man codeine is principally metabolized by O- and N-demethylation and glucuronidation. Codeine-6-glucuronide is the major metabolite, accounting for approximately 50 % of the dose in the urine [Adler et al. 1955; Chen et al. 1991; Yue et al. 1989]. Paracetamol is metabolized in a similar manner to codeine, by oxidation and by sulphate and glucuronide conjugation, the latter being quantitatively the most important [Prescott et al. 1980]. The oxidative metabolism of both substances is of particular significance. Oxidation of paracetamol results in the formation of a reactive toxic quinone-imine meta-
bolite, and the oxidative O-demethylation of codeine yields the pharmacologically active analgesic morphine (and its active 6-glucuronide). If glucuronidation of either compound is substantially reduced, shunting of metabolism through oxidation could become quantitatively much more important, with the potential for clinical toxicity. It has been reported that therapeutic doses of codeine do not influence the absorption [Bajorek et al. 1978; Persaud et al. 1985; Burgess et al. 1985; Klein et al. 1986], clearance, or metabolism of paracetamol [Sonne et al. 1988]. However, it is not known whether paracetamol has any effect on codeine metabolism. The aim of this study was to determine the effect of chronic administration of paracetamol on the metabolism and disposition of codeine in healthy human subjects.
Materials and methods Subjects
Six healthy subjects, 3 men and 3 women, participated in the study, which was approved by the Human Ethics Committee of the Royal Adelaide Hospital and the Committee on the Ethics of Human Experimentation of the University of Adelaide. The subjects were aged 29.0 (9.5) y (mean (SD), range 18-44) y and weighed 71.0 (9.1) kg (range 61-86) kg. Other medications were prohibited for two weeks before codeine administration and for the duration of the study. Alcohol and tobacco were not used for 48 h before each dose and during the study. Since codeine O-demethylation to morphine exhibits genetic polymorphism [Chen et al. 1988;Yue et al. 1989],poor metabolizers, assessed using dextromethorphan [Chen et al. 1990], were excluded.
Study design Phase 1. After a 10 h overnight fast, each subject took a single tablet of 30 mg codeine phosphate (Fawns & McAllan Pty. Ltd., Croydon, Australia), equivalent to 22.8 mg (76.2 btmol) codeine base, with 100 ml of water. Food was permitted after 3 h and normal fluid intake was allowed. The subjects were ambulant but confined to the laboratory for the 12 h of sampling. Venous blood samples (8 ml)
380
A. Somogyi et al.: Codeine kinetics and paracetamol
Table 1, Pharmacokinetic data for codeine and codeine-6-glu-
jects who took 30 mg codeine phosphate alone (I) and with paracetamol 1 g 8 hourly for 7 doses (II)
curonide and apparent partial clearances of codeine to codeine-6glucuronide (C-6-G), morphine, and norcodeine in 6 healthy subCmax(nmol. 1 ')
tmax(h)
I
I
II
I
II
0.75 0.22 NS
0.92 0.34
2.20 0.24 NS
2.23 0.34
0.81 0.21 NS
1.25 0.50 NS
1.25 0.39
2.43 0.63 NS
2.39 0.45
22.0 9.7 NS
II
t~a (h)
AUC (gmol. 1-~. h)
CLR (ml. min- 1)
I
I
II
II
Codeme Mean SD
243 29 NS
271 86
0.84 0.32
252 74 NS
291 106
29.7 9.4 NS
39.6 18.7
Codeme-6-glucuronide Mean SD
5289 2553 NS
5677 4081
21.9 11.0
Apparent partial clearances (mI. rain ~) C-6-G Mean SD
Morphine
Norcodeine
M + N + C-6-G"
I
II
I
II
I
II
I
II
820 386 NS
1022 416
88 42
70 30
71 30
88 39
979 373 NS
1181 428
NS
NS
M + N + C-6-G:sumofapparentpartialclearancestomorphine,norcodeine, and codeine-6-glucuronide NS:notsignificant(P >0.05) were collected into heparinized plastic tubes at 0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, and 12 h after codeine via an indwellingcatheter in a forearm vein kept patent with a stylet (Jelco TM, Critikon Inc., Tampa, USA). All urine was collected in 0-12, 12-24, and 24~8 h aliquots after dosing.
AUC = AUC0--+12 + CIast/;Lz
Phase 2. Each subject took 7 doses of paracetamol (Panadol®, Win-
Renal clearance (CLR) was calculated as:
throp Laboratories, Ermington, Australia) i g 8-hourly orally. The seventh dose was given in combination with 30 mg codeine phosphate and the same procedures were adopted as in phase 1. The order of the two phases was evenly randomized and the phases were separated by a 7-day interval. Plasma was separated by centrifugation. Urine pH and volume were recorded and an aliquot (10 ml) was retained for analysis. All samples (plasma and urine) were stored in stoppered vials at - 20 °C until analysis.
Drug analyses Codeine concentrations in plasma and urine were determined by a high performance liquid chromatographic (HPLC) method [Chen et al. 1989a]. The limit of detection was 2ng-ml ~ for codeine (6.7 nmol-1 1) in plasma and 0.1 gg.ml -I (0.33 btmol.1-1) in urine. Total (unconjugated + conjugated) norcodeine and morphine concentrations in urine were determined by the above method after [3glucuronidase hydrolysis. The limit of detection was 0.1 ~,g.ml-1 (0.35 btmol. 1 ~) for morphine and norcodeine in urine. Codeine-6glucuronide was determined directly in plasma and urine by HPLC [Chen et al. 1989b]. The limits of detection were 10ng-ml (21 nmol. 1 ~) in plasma and 0.1 btg ml-1 (0.21 btmol. 1 1) in urine. Paracetamol and its metabolites did not interfere with these analyses.
Pharmacokinetic and statistical analyses The maximum plasma concentration (Cm,x) and its time of occurrence (tma~)were determined from the observed data. The elimination rate constant (G) was calculated from the slope of the terminal portion of the semilogarithmic plasma concentration-time curves. The area under the plasma concentration-time curves to the last sampling time (AUC0--+12)was calculated by the linear trapezoidal method and the total AUC was calculated as:
where Cl,~tin the plasma concentration at 12 h. Half-life (h/2) in plasma was calculated as: tl/2 = ln2/~z
CLa = Ae/AUC where Ae was the amount excreted unchanged between 0 and 48 h. The apparent partial metabolic clearances (CLm) of codeine to its measurable metabolites (morphine, norcodeine, and codeine-6-glucuronide) were calculated as: CL~ = Aem/AUC where Aem for morphine is morphine and morphine conjugates excreted in urine, Aem for norcodeine is norcodeine and norcodeine conjugates in urine, and Aem for codeine-6-glucuronide is the amount of codeine-6-glucuronide recovered in the urine. These were all expressed in terms of codeine base. Differences in pharmacokinetic data between treatments were analysed for statistical significance by Student's paired t-test. P < 0.05 was chosen as the level of statistical significance. Linear regression was used for correlation analysis. All data are reported as mean (SD).
Results
T h e derived p h a r m a c o k i n e t i c data are listed in Table 1. T h e r e were n o significant differences in c o d e i n e a n d cod e i n e - 6 - g l u c u r o n i d e disposition b e t w e e n the two treatments. T h e r e was a significant c o r r e l a t i o n b e t w e e n the r e n a l clearance of c o d e i n e a n d u r i n e p H (r =0.73, P < 0.01), b u t n o c o r r e l a t i o n with the r e n a l clearance of c o d e i n e - 6 - g l u c u r o n i d e (r = 0.49, P > 0.05). T h e r e was n o c o r r e l a t i o n b e t w e e n u r i n e flow rate a n d the r e n a l clearances of c o d e i n e (r = 0.27, P > 0.05) or codeine-6-gluc u r o n i d e (r = 0.40, P > 0.05). T h e a p p a r e n t partial m e t a b o l i c clearances of c o d e i n e to c o d e i n e - 6 - g l u c u r o n i d e , m o r p h i n e , a n d n o r c o d e i n e
381
A. Somogyi et al.: Codeine kinetics and paracetamol 100-
l
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iiiiii{i{ii
iiiiiiiiii!ii!!i ~ii!iiiiii
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Fig.1. Urinary recoveries of codeine and its metabolites as a percentage of the dose in 6 healthy subjects who received 30 mg codeine phosphate alone (open) and with paracetamol 1 g 8 hourly for 7 doses (stippled). C-6-G is codeine-6-glucuronide
were not significantly altered by the co-administration of paracetamol (Table 1). The 95 % confidence intervals of the ratio of the partial clearances to codeine-6-glucuronide in the two treatments were 0.56 to 1.10, for the partial clearance to morphine the confidence intervals were 0.80 to 1.98, and for the partial clearance to norcodeine the confidence intervals were 0.40 to 1.34. The urinary recoveries of codeine, codeine-6-glucuronide, total (unconjugated + conjugated) norcodeine, and total morphine as percentages of the administered dose in the six subjects are shown in Fig. 1. There were no statistically significant differences between the two phases.
Discussion
In man, multiple isozymes of the UDP-glucuronosyltransferases have been isolated [Burchell and Coughtrie 1989; Tephly and Burchel11990]. However, it is not known by which form paracetamol and codeine are conjugated. The lack of inhibition of codeine glucuronidation by paracetamol suggests that the glucuronidation of each substance is probably mediated by different forms of UDP-glucuronosyltransferases. This is further supported by the observations in human liver microsomes, in that whereas morphine did not inhibit paracetamol glucuronidation [Miners et al. 1990], it did inhibit the glucuronidation of codeine [Yue et al. 1990]. The renal clearances of codeine and codeine-6-glucuronide appear to be mediated by different mechanisms. The renal clearance of codeine is via filtration at the glomerulus, active tubular secretion, and passive reabsorption in the distal tubule and collecting duct, the latter being pH-dependent, as we have previously reported [Chen et al. 1991]. Neither paracetamol nor its metabolites altered the renal clearance of codeine. The renal clearance of codeine-6-glucuronide is by filtration at the glomerulus and reabsorption, possibly by a carrier-mediated process, as renal clearance was less than that accounted for by the unbound fraction multiplied by the glomerular filtration rate [Chen et al. 1991]. An alternative hypothesis is that it is deconjugated in the kidney, but there is no evidence to substantiate this. The lack of effect ofparacetamol and/or its metabolites on the renal clearance of codeine-6-glucuronide suggests that the apparent reabsorption of codeine-6-glucuronide may be mediated by a unique transport system. In conclusion, the results show that paracetamol has no effect on the pharmacokinetics or metabolism of codeine in healthy human subjects and that any additive pharmacodynamic effect is not the result of a pharmacokinetic interaction between these two analgesics. Acknowledgements. Dr. Chen is a Florey Research Fellow of the Royal Adelaide Hospital. This study was supported by Sterling Pharmaceuticals Pty. Ltd. (Ermington, Sydney,Australia). We thank Cathy Danz, R.N. for help with the clinical aspects of the study.
and conclusions References
The pharmacokinetics of codeine and codeine-6-glucuronide obtained in this study are similar to those reported previously [Findlay et al. 1977, 1978, 1986; Rogers et al. 1982; Quiding et al. 1986; Bodd et al. 1987; Chen et al. 1991]. The pharmacokinetics (AUC, tla, CLR) of codeine were not altered by paracetamol. The oxidative metabolism of codeine to morphine is catalysed by cytochrome P450 IID6 (P450 dbl) [Dayer et al. 1988], and paracetamol had no inhibitory or stimulatory effect on this enzyme, as measured by the partial clearance rate to morphine, although there was substantialvariability in the data. These results support in vitro human microsome data, which show a lack of inhibition by paracetamol on this oxidative pathway (unpublished observations). The N-demethylation of codeine to norcodeine, which is catalysed by a different form(s) of cytochrome P450 was also not inhibited by paracetamol, as shown by the unaltered partial metabolic clearance to norcodeine.
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