It appears probable that the metabolism of both terodiline and prenylamine may be mediated by the P450 cytochrome CYP2D6, the isoform responsi-ble for debrisoquine hydroxylation.
POLYMORPHIC CYP2D6-MEDIATED
STEREOSELECTIVE METABOLISM
It
appears probable that the metabolism of both terodiline and prenylamine may be
mediated by the P450 cytochrome CYP2D6, the isoform responsi-ble for
debrisoquine hydroxylation. This major drug-metabolizing isozyme is expressed
polymorphically in all populations, resulting in two major drug-metabolizing
phenotypes – extensive (EM) and poor (PM) metabolizers. The latter are unable
to effect the metabolic elimination of CYP2D6 substrates, and these include
antiarrhythmic agents, β-blockers, anti-hypertensive drugs, neuroleptics and
antidepressants. Consequently, PM individuals are exposed to higher
concentrations of the parent drug for longer duration.
The
pharmacokinetics of prenylamine are enan-tioselective, favouring the elimination
of the + - (S)-enantiomer
(Gietl et al., 1990; Paar et al., 1990). On multiple dosing, the
apparent oral clearance of the (+) -(S)-enantiomer
was 4.6-fold and the renal clearance 2.4-fold higher than that of the (−) -(R)-enantiomer. The
maximum plasma concentration and AUC (area under curve of plasma concentration
vs. time) of the (+)
-(S)-enantiomer
were 4–5 times lower than those of the (−) -(R)-enantiomer. After a single dose,
the mean plasma half-lives of −
- (R)-prenylamine and (+) -(S)-prenylamine
were 8.2 and 24 hours, respectively. On chronic dosing, the mean half-lives for
(−) -(R)-prenylamine and (+) -(S)-prenylamine were
reported to be 13.7 and 17.4 hours, respectively (Gietl et al., 1990). However, the appar-ently only slightly higher mean value
of the half-life of (+) -(S)-enantiomer
following a single dose was mainly a consequence of its extremely long plasma
half-lives of 82 and 83 hours in 2 of the 8 volun-teers. The remaining 6
subjects showed an average half-life of 11 hours. Although none of these
subjects had been phenotyped for their CYP2D6 metabolic capacity, prenylamine
fulfils all the structural require-ments of a CYP2D6 substrate and it is worth
spec-ulating whether these two individuals were PMs of CYP2D6 with an impaired
ability to eliminate (+) -(S)-prenylamine.
Patients with prenylamine-induced proarrhythmias have not been genotyped or
pheno-typed for their CYP2D6 metabolizing capacity.
Studies
with rat liver microsomes suggest that more than one CYP isoform may be
involved in the metabolism of terodiline, with different isoforms mediating the
metabolism of the two enantiomers (Lindeke et
al., 1987). In studies using human liver microsomes, the metabolism of
terodiline at high concentrations has been shown to be stereoselec-tive
favouring the (+)
-(R)-enantiomer
(Noren et al., 1989), although the
ratio of concentrations of the two enantiomers at steady-state following
administration of clinical doses is close to unity (Hallen et al., 1995).
Although
much of the data in man are incom-plete, puzzling or often difficult to
reconcile, there is fairly persuasive evidence to suggest that the major
isozyme involved in the metabolism of (+) -(R)-terodiline is CYP2D6, and therefore
the metabolism of (+)
-(R)-terodiline
is subject to genetic polymor-phism. The formation of p-hydroxy-terodiline from
-(R)-terodiline was found to be impaired in one PM of debrisoquine (Hallen et al., 1993). In this study of the pharmacokinetics of a 25 mg
oral dose of + - (R)-terodiline in
healthy volunteers, the mean half-life of this enantiomer in 4 EMs of
debrisoquine was 42 (range 35–50) hours and in the only PM in this study, it
was 117 hours. In another study (Thomas and Hartigan-Go, 1996) in healthy
volunteers, which included 7 EMs and 2 PMs who were administered a single oral
dose of 200 mg racemic terodiline, the maximum plasma concentrations and AUC of
+ - (R)-terodiline
were significantly higher compared with − -(S)-terodiline, although their
half-lives were similar. Even at this high dose (which would be expected to
conceal the pharmacokinetic difference between the two genotypes), the PM/EM
clearance ratios for (+) -(R)-terodiline
and − -(S)-terodiline
were 45% and 56%, respectively. In common with all drugs subject to polymorphic
metabolism, the phar-macokinetic difference between the EMs and the PMs are
less evident at higher doses because of increasing saturation of metabolism in
EMs at higher doses.
It
is worth pointing out that the (+) -(R)-enantiomer
of tolterodine (a structural analogue of terodiline) with anticholinergic
properties is marketed for the treat-ment of urinary incontinence. Its
oxidative hydroxyla-tion has been confirmed in in vitro and in vivo
studies to be mediated principally by CYP2D6 (Brynne et al., 1998; Postlind et al.,
1998). CYP3A4-mediated dealkylation
provides a major alternative, albeit less effective, route of elimination in
those who are PMs of CYP2D6 (Brynne et al.,
1999).
The
consequence of this stereoselective and (most probably) polymorphic metabolism
is that the calcium antagonistic − -(S)-terodiline would accumulate in
all patients over time, but in addition there will also be an accumulation of
the anticholinergic (+) -(R)-terodiline
in the poor and intermediate metabolizers of CYP2D6 substrates. Thus,
genetically determined accumulation of (+) -(R)-terodiline could constitute another
risk factor. While it is true that the doses used in Sweden and Japan were
generally lower, this CYP2D6-mediated metabolism of (+) -(R)-terodiline might
also explain the striking inter-ethnic differences in the incidence of
ventricular arrhythmias associated with its use. Whereas 9% of the UK
population are PMs, the corresponding figures for Sweden and Japan are only
6.8% and less than 1%, respectively. The higher frequency of PM alleles in the
UK population will necessarily result in a higher prevalence of the
heterozygous CYP2D6 genotype – a subgroup most at risk of drug–drug
interactions – and therefore give rise to a higher potential for drug–drug
interactions in the United Kingdom between terodiline and other QT
interval-prolonging substrates of CYP2D6, such as neuroleptics, antidepressants
and other antiarrhyth-mic drugs.
Ford,
Wood and Daly (2000) investigated the roles of CYP2D6 and CYP2C19 genotypes in
eight patients who survived terodiline-induced proarrhyth-mias (six with
torsade de pointes and two with ventric-ular tachycardia). One of these eight
patients had a CYP2D6 PM genotype, and it was observed that CYP2D6 alleles were
no more frequent in these eight individuals than in the normal population. This
study also found a statistically higher frequency of the mutant CYP2C19∗2 allele in this population. As a result, these
investigators suggested that whereas CYP2D6 PM status was not a risk factor for
terodiline cardiotoxicity, possession of the CYP2C19∗2 allele might contribute to adverse cardiac reactions to
terodi-line. This study, however, has serious limitations that the
investigators themselves have acknowledged. Only two mutant alleles of CYP2D6
were looked for and there was no ECG evidence confirming the adverse drug
response phenotype (i.e. the presence of QT interval prolongation or torsade de
pointes). There was a lack of information on co-medications in 2 patients. In
another 2 patients, there was co-administration of diuretics that may
predispose to hypokalaemia, and therefore to torsade de pointes.
It
may be speculated whether any of the 12 patients with terodiline-induced
proarrhythmias reported to the CSM, and in whom there were no obvious risk
factors may have had a phar-macogenetic defect in their CYP2D6-mediated drug
metabolism of (+)
-(R)-terodiline.
Connolly et al., (1991) and Andrews
and Bevan (1991) have also reported one case each of torsade de pointes in
patients without any risk factors and in whom plasma terodiline levels were
markedly elevated. Informa-tion on the genotypes of such patients would
have been more helpful in elucidating
the role of (pharma-cokinetic) genetic susceptibility to terodiline-induced
proarrhythmias.
In
addition, the susceptibility role of CYP2C19∗2 suggested by Ford,
Wood and Daly (2000) does not explain either the absence of terodiline
cardiotoxicity among the Japanese (in whom the frequency of the CYP2C19∗2 allele is much higher at 0.29–0.35), or the high frequency
of anticholinergic effects medi-ated by (+) -(R)-terodiline in Scandinavia (where
the frequency of the CYP2C19∗2 allele is far
lower, at no more than 0.08). There is also the evidence show-ing that the
frequency of this allele is not any higher among the elderly (Yamada et al., 1998), who were the target
population for the use of terodiline. Neither can the closely related CYP2C9
isoform be implicated. Terodiline 50 mg daily did not influence the plasma
levels of warfarin enantiomers, nor the anticoagulant effect, following
continuous daily administration of a mean dose of 5.3 mg warfarin (Hoglund,
Paulsen and Bogentoft, 1989).
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