Protecting the poor metaboliser--from what?
- British journal of clinical pharmacology
Dear Sir, Dr. Jack and his colleagues have castigated us in the correspondence columns of several journals for seeking to 'protect the poor metaboliser', particularly in respect to the use of metoprolol (Jack et al. 1983a, b, c, d; Jack and Wilkins 1984). Although our definitive reply has recently appeared in the British Journal of Clinical Pharmacology (Lennard et al. 1984), we list here some of the salient points: 1. The contribution of oxidative polymorphism to the overall elimination of metoprolol is not small (Lennard et al. 1983). 2. Although variability in the plasma concentrations of lipid-soluble drugs is common, at least in some cases it is now possible to explain much of this variability on the basis of genetic control of drug oxidation. 3. Large variability in the plasma concentrations of many drugs may not be dangerous but it may be sufficient to cause non-complitance if so-called minor side-effects are ignored by the physician. Adjustment of drug dosage on the basis of clinical effects is difficult even for the careful physician. 4. Adverse drug reaction monitoring schemes are not controlled prospective studies and often concentrate on more serious drug effects rather than troublesome 'side-effects'. Although there is no evidence of a greater incidence of the latter using drugs with wide variability, such as propranolol and metoprolol, compared to polar drugs like atenolol, neither is there good evidence that there are no differences. Until the appropriate studies are done it would seem prudent to keep an open mind. 5. Relationships between plasma concentrations of beta-blockers, decrease in exercise heart rate and control of angina are well-established. The fact . that PM's and EM's of metoprolol show 3-4 fold differences in degree of beta-blockade at 24 h after a standard dose has obvious implications for the choice of dosage interval and the need, or otherwise, for sustained-release dosage forms. On the other hand, no amount of pharmaceutical technology will offset a 6-fold difference in AUC in PM's and EM's of metoprolol. Variability in plasma drug concentrations is certainly no justification for denying the benefits of a drug either retrospectively once it is on the market or prospectively during its development. However, other factors being equal and if there is a choice of compound, those showing less variability may be easier to use and should be preferred.