If you wish to respond to a paper or other item already published in the BJA, please go to the abstract/full text version of that item and click on the link "E-Letters: Submit a response to the article".
Electronic Letters to:
|
|
E-letters: Electronic letters published:
-
![[Read E-letter]](/icons/misc/sectionDOWN.gif)
Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma
- Johannes H. Proost (7 February 2005)
|
|
|||
|
Johannes H. Proost
Send letter to journal:
|
Recently, Kotb and colleagues reported a study on the pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma [1]. I would like to make some comments on this paper. 1) The authors fitted a two-compartment model to the morphine concentrations (they erroneously write that ‘morphine concentrations were fitted to a two-compartment model’), ‘where total body clearance (Cl) and bioavailability (F) were calculated’. Since the authors used only data from oral administrations, Cl and F cannot be calculated; only their ratio Cl/F can be obtained from the data. Nevertheless, mean values of Cl and F are reported in Table 1. 2) Morphine undergoes considerable first-pass effect in the liver, at least in normal subjects. Probably the authors estimated F from the observed ratio Cl/F, assuming a model for liver extraction, e.g. the well- stirred model, and estimates of hepatic blood flow and blood-to-plasma ratio [2]. However, this is not described in the manuscript. 3) If the authors applied the aforementioned procedure to estimate F and Cl, the reported values imply that the hepatic blood flow in both liver carcinoma patient groups is more than two times higher than that in control patients. This seems rather unlikely. It should be noted that such a procedure provides estimates of F and Cl that are dependent on the selected hepatic extraction model [2-4]. 4) The data were analysed using a pharmacokinetic model with first- order absorption. However, the concentration profiles depicted in Figure 2 suggest a zero-order absorption over the time period until three hours after administration, in particular for the two patient groups. In addition, the dosage form MST was designed for controlled release of morphine, likely resulting in a ‘close-to-zero order’ release kinetics. Therefore it is not logical to assume a first-order absorption rate constant in the pharmacokinetic model. 5) The data were analysed using a two-compartment pharmacokinetic model. The concentration profiles depicted in Figure 1 do not suggest that a two-compartment should be preferred over a one-compartment model. The paper does not describe any justification for using the two-compartment model. 6) Fitting the parameters of a two-compartment model with an absorption phase is cumbersome. There are always two equally valid solutions for the model, and identification of the absorption rate constant is not possible. 7) In addition, the estimation of five parameters from twelve data points is cumbersome from a statistical point of view. A population approach would be more appropriate to obtain reliable parameter estimates. The same comments apply to an earlier paper of the same authors [5], in which they described the pharmacokinetics of controlled release morphine (MST) in patients with liver cirrhosis, also providing the data of the control group of the current paper (cited as reference 6). References 1. Kotb HIM, El-Kady SA, Emara SES, Fouad EA, El-Kabsh MY. Pharmacokinetics of controlled release morphine (MST) in patients with liver carcinoma. Br J Anaesth 2005; 94: 95-9 2. Rowland M, Tozer TN. Clinical pharmacokinetics - Concepts and applications, 3rd Edition. Media PA, Williams and Wilkins, 1995. 3. St-Pierre MV, Lee PI, Pang KS. A comparative investigation of hepatic clearance models: predictions of metabolite formation and elimination. J Pharmacokinet Biopharm 1992; 20:105-45 4. Hussein Z, Evans AM, Rowland M. Physiologic models of hepatic drug clearance: influence of altered protein binding on the elimination of diclofenac in the isolated perfused rat liver. J Pharm Sci 1993; 82: 880-5 5. Kotb HIM, El-Kabsh MY, Emara SES, Fouad EA. Pharmacokinetics of controlled release morphine (MST) in patients with liver cirrhosis. Br J Anaesth 1997; 79: 804-6 Johannes H. Proost Department of Pharmacokinetics and Drug Delivery Groningen University Institute for Drug Exploration (GUIDE) University of Groningen, The Netherlands & Research Group for Experimental Anaesthesiology and Clinical Pharmacology Department of Anaesthesiology University Medical Centre Groningen, The Netherlands Correspondence: Antonius Deusinglaan 1 9713 AV Groningen The Netherlands e-mail: j.h.proost@rug.nl Conflict of Interest:None declared |
|||