Chapter 17 - Page 2

Linear Plot of Morphine Concentration versus Time after Codeine Administration

Try simulating morphine concentration versus time after oral codeine administration. Select individuals with low, intermediate or high CYP2D6 activity. Add additional lines with different parameter values using the Add Line button.

Figure 17.2.1 A Simplified Pharmacokinetic Model for Codeine Transformation into Morphine

The model in Figure 17.2.1 is a simplification of codeine and morphine pharmacokinetics. Codeine is metabolized to a variety of compounds including morphine. Also, both codeine and morphine are probably better described using a two compartment model.

The lines in the plot above were calculated using Equation 17.2.1, derived from the model, Figure 17.2.1, for codeine metabolism using Laplace transforms.

Equation 17.2.1 Concentration of Morphine after Oral Administration of Codeine

Table 17.2.1 Some Parameters Describing Codeine Metabolism

Parameter	Value	Units
Dose	30	mg
F	0.5¹
ka	2.28²	hr^-1
kel (codeine)	0.21¹	hr^-1
V (codeine)	3.45 x 70 = 242¹	L
V (morphine)	70¹	L
kel (morphine)	0.3¹	hr^-1
km (high)	0.013⁵	hr^-1
km (intermediate)	0.0065⁹	hr^-1
km (low)	0.0006¹⁰	hr^-1

References and Notes

¹Ritschel, W.A. and Kearns, G.L. 2004 Handbook of Basic Pharmacokinetics ... including Clinical Applications, 6th ed., American Pharmaceutical Association, Washington, DC ISBN 1-58212-054-4
²Estimated from kel and t_max (1.1 and 1.2 hr)^3,4
³Band, C.J., Band, P.R., Deschamps, M., Besner, J.G. and Coldman, A.J. 1994 Human pharmacokinetic study of immediate-release and sustained-release codeine, J. Clin. Pharmacol., 34, 938-43
⁴Shah, J.C. and Mason, W.D. 1990 Plasma codeine and morphine concentrations after a single oral dose of codeine phosphate, J. Clin. Pharmacol., 30, 764-6
⁵Estimated from kel and fe (0.071, 0.051 and 0.065)^6,7,8
⁶Chen, Z.R., Somogyi, A.A., Reynolds, G. and Bochner, F. 1991 Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers, Brit. J. Clin. Pharmacol., 31, 381-90
⁷Vree, T.B. and Verwey-van Wissen, C.P. 1992 Pharmacokinetics and metabolism of codeine in humans, Biopharm. Drug Disposit., 13, 445-60
⁸Hendenmalm, K., Sundgren, M., Granberg, K., Spigset, O. and Dahlqvist, R. 1997 Urinary excretion of codeine, ethylmorphine, and their metabolites: Relation to the CYP2D6 activity, Therap. Drug Monitor., 19, 643-9
⁹Estimated as 0.5 x km (high)
¹⁰Estimated from km (high) and plasma and urine ratios (1:0.034 and 0.058)^11,6
¹¹Desmeules, J., Gascon, M.P., Dayer, P. and Magistris, M. 1991 Impact of environmental and genetic factors on codeine analgesia, Eur. J. Clin. Pharmacol., 41, 23-6

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