Introduction
Large differences have been shown to exist between different species
and among different individuals within one species, including
man, in their capacity to metabolise drugs and other xenobiotics.
This substantial inter-individual variability is caused by genetic
and environmental factors and translates into major differences
between human subjects in the rate at which drugs are eliminated
from the body (metabolic clearance). The basal rate of drug metabolism
in a certain individual is determined by genetic constitution,
but it varies in addition with age, gender and environmental factors
like diet, disease states, concurrent use of other drugs or exposure
to certain xenobiotics (inducing or inhibiting drug metabolising
enzyme activity).
The CYP450 system
Metabolism of most currently used drugs takes place by oxidation
as a primary step and the Cytochrome P450 enzyme family (P450)
is catalyzing this. In recent years around 30 human P450s have
been identified, of which at least 7 play a clinically relevant
role in drug (xenobiotic) metabolism. These are CYP1A2, CYP2C8,
CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP2E1. These enzymes catalyse
different reactions and have different (but partially overlapping)
catalytic specificity with respect to substrate and to product
formation. In Figure 1 the circles schematically represent the
different human CYP450s, with their "probe" substrates
and (selective) inhibitors.
Figure 1. Schematic presentation of human CYP450 enzymes with model substrates and selective inhibitors (Breimer 1994)
The size of the circles does not represent the relative amount of that CYP450 present in human liver under healthy conditions. In fact, CYP3A4 is the most abundant with about 25% of the total P450 and CYP1A2, CYP2C8 and CYP2C9 with each around 10%, CYP2D6 and CYP2E1 each around 5% and CYP2C19 around 1%. All enzymes exhibit major variability in their activity (10- to more than 100-fold) between different subjects, which is partially caused by genetic factors (in particular for those enzymes exhibiting genetic polymorphism: CYP2D6 and CYP2C19) and by environmental factors. For many important drugs it is currently known by which enzyme they are metabolized and that knowledge is a prerequisite for new drugs entering clinical practice. Several opioid derived drugs are metabolized by CYP2D6 as a first step, often leading to pharmacologically active metabolites. The absence of CYP2D6 activity may therefore have important implications.
CYP2D6 and opioid metabolism
CYP2D6 has clearly been shown to exhibit true genetic polymorphism
and several different CYP2D6 alleles have been identified which
explains the existence of poor metabolizers, extensive metabolizers
and ultra-extensive metabolizers. Currently genoty-ping has become
feasible to differentiate between such categories. For phenotyping
purposes often debrisoquine, sparteine or the antitussive opioid
dextromethorphan are used, by determining their parent drug to
metabolite ratio in an 8 hour's urine sample after single dose
administration. Oxidative dealkylation of several opioids is catalyzed
by CYP2D6, i.e. codeine, dihydrocodeine, ethylmorphine, hydrocodone
and oxycodone. For codeine it has clearly been demonstrated that
its analgesic effect is mediated by the formation of its active
metabolite morphine (Poulsen et al., 1996). In poor metabolizers
(PMs) hardly any morphine is formed and therefore PMs (6-10% of
the Caucasian population) do not enjoy beneficial analgesic effects
after codeine administration. On the other hand PMs do not suffer
from constipative effects of codeine, whereas extensive metabolizers
(EMs) do because of morphine formation (Mikus et al., 1997). The
incidence of other adverse effects after codeine administration
seems to be similar for EMs and PMs of CYP2D6 (Eckhardt et al.,
1998).
References
1. D.D. Breimer (1994). Genetic polymorphism in drug metabolism:
clinical implicati-ons and consequences in ADME studies. In: The
Relevance of Ethnic factors in the Clinical Evaluation of Medicines
(S. Walker et al., eds). Kluwer Academic Publis-hers (Dor-drecht/Boston),
pp.13-26.
2. K. Eckhardt et al. (1998). Same incidence of adverse drug events
after codeine administ-ration irrespective of the genetically
determined differences in morphine formation. Pain 76, 27-33.
3. G. Mikus et al. (1997). Effect of codeine on gastrointestinal
motility in relation to CYP2D6 phenotype. Clin. Pharmacol. Ther.
61, pp. 459-466
4. L. Poulsen et al. (1996). Codeine and morphi-ne in extensive
and poor metabolizers of sparteine: pharmacokinetics, analge-sic
effect and side effects. Eur. J. Clin. Pharmacol. 51, pp. 289-295