It appears probable that the metabolism of both terodiline and prenylamine may be controlled by the P450 cytochrome CYP2D6, the isoform responsible for debrisoquine hydroxylation. This major drug metabolising isozyme is expressed polymorphically in a population, resulting in two major phenotypes: extensive (EM) and poor (PM) metabolisers. The latter are unable to effect the metabolic elimination of many CYP2D6 substrates which include antiarrhythmics, ^-blockers, antihypertensives, neurolep-tics and antidepressants.
On chronic dosing, the half-lives for the (—)-(R)-and (+)-(S)-prenylamine were 13.7 and 17.4, hours respectively (Geitl et al., 1990). Generally, the steady-state plasma level was reached after 5 -7 days indicating that the terminal half-lives of both the enantiomers of prenylamine were in the region of 24 hours. The high average value for the (+)-(S)-enantiomer following a single dose was mainly a consequence of the extremely long plasma halflife of 82 and 83 hours in 2 of the 8 volunteers. The remaining 6 subjects showed an average half-life of 11 hours. Although none of these subjects had been phenotyped for their metabolic capacity, prenylamine fulfils all the structural requirements of a CYP2D6 substrate and it is worth speculating whether the two individuals were poor metaboli-sers of CYP2D6 with an impaired ability to eliminate (+)-(S)-prenylamine.
Studies with rat liver microsomes suggest that more than one CYP isoform may be involved in the metabolism of terodiline, with different iso-forms involved for the two enantiomers (Lindeke et al., 1987). Although much of the data in man are incomplete, puzzling or often difficult to reconcile, there is a fairly persuasive body of evidence to suggest that the major isozyme involved in the metabolism of (+)-(R)-terodiline is CYP2D6 and hence subject to genetic polymorphism. The formation of p-hydroxy-terodiline from (+)-(R)-terodiline was found to be impaired in one poor metaboliser of debrisoquine (Hallen et al., 1993). In this study of the pharmacokinetics of 25 mg oral dose of (+)-(R)-terodiline in healthy volunteers, the mean half-life of the isomer in 4 EMs of debrisoquine was 42 (range 35-50) hours and in the only PM, it was 117 hours. In another study (Thomas and Hartigan-Go, 1996) in healthy volunteers, which included 7 EMs and 2 PMs 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)-terodi-line and their half-lives were similar. The PM/EM clearance ratios for (+)-(R)-terodiline and (—)-(S)-terodiline were 45% and 56%, respectively.
Oxidative hydroxylation of the R-enantiomer of tolterodine, a new structural analogue of terodiline with antimuscarinic properties and marketed for the treatment of urinary incontinence, has also been shown in vitro and in vivo studies to be mediated principally by CYP2D6 (Brynne et al., 1998; Postlind et al., 1998), with CYP3A4-mediated dealkylation providing the main route of elimination in those who are the PMs of CYP2D6 (Brynne et al., 1999).
However, in a study investigating the stereo-selective cardiotoxicity of terodiline in healthy volunteers given high doses, elimination of terodi-line enantiomers was not significantly delayed in two genotypic PMs of CYP2D6 (Hartigan-Go et al., 1996). Another study of the CYP2D6 and CYP2C19 genotypes of 8 patients who survived terodiline-induced proarrhythmias, 6 with torsades de pointes and 2 with ventricular tachycardia, concluded that the CYP2D6 alleles were no more frequent in these 8 individuals than in the normal population (Ford et al., 2000). This study also found a statistically higher frequency of mutant CYP2C19 *2 allele in this population and it was suggested that CYP2D6 poor metaboliser status was not primarily responsible for terodiline cardiotoxicity and that possession of the CY-P2C19 *2 allele appeared to contribute to adverse cardiac reactions to terodiline. This study has serious limitations that have been acknowledged by its authors, and among others include the lack of ECG evidence of QT interval prolongation or torsade de pointes, lack of information on co-medications in 2 patients and co-administration of diuretics in another 2 patients.
The susceptibility role of CYP2C19 *2 suggested by Ford et al. (2000), however, 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 of (+)-(R)-terodiline in Scandinavia, where the frequency of the CYP2C19 *2 allele is far lower at no more than 0.08. Neither is there any evidence that the frequency of this allele is any higher among the elderly. Neither can the closely related CYP2C9 isoform be implicated. Terodiline 50 mg daily did not influence the anticoagulant effect of continuous daily administration of a mean dose of 5.3 mg warfarin or the plasma levels of the warfarin enantiomers (Hoglund et al., 1989).
It is worth recalling that, among the 69 cases of terodiline-induced proarrhythmias reported to the CSM, there were 12 in whom there were no identifiable risk factors. Connolly et al. (1991) and Andrews and Bevan (1991) have also reported one case each of torsades de pointes in patients without any risk factors and in whom plasma terodiline levels were markedly elevated. Information on the genotypes of such patients would have been helpful in elucidating the role of genetic susceptibility to terodiline-induced proarrhythmias.
The consequence of this stereosensitive 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 (+)-(R)-terodiline in the poor and intermediate CYP2D6 metabolisers.
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)-terodi-line 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 2.5% and less than 1%, respectively. Such a metabolic pattern would indicate a high potential for drug-drug interaction in the United Kingdom between terodiline and other QT interval prolonging substrates of CYP2D6, such as neuroleptics, antidepressants and other antiarrhythmic drugs.
Mutations of potassium channels, resulting in diminished repolarisation reserve and increased pharmacodynamic susceptibility to prolongation of the QT interval, are common. Female gender is a particularly striking example of genetically conferred susceptibility. Furthermore, any cardiac disease-induced down-regulation of potassium channels will also increase this susceptibility to proarrhythmias. Genetic factors may also operate remotely through other mechanisms. For example, cardiac failure is the end result of many genetically (and non-genetically) determined cardiac diseases. Cardiac failure is typically associated with such a down-regulation. It is interesting to note that despite urinary incontinence, 27 of the 69 patients with terodiline-induced proarrhythmias analysed above were receiving diuretics and 33 were in receipt of other cardioactive medications. Hypoka-laemia induced by these diuretics or electrophysio-logical activities of these cardioactive medications further potentiate pharmacodynamic susceptibility. In addition, there is increased susceptibility to QT prolonging drugs in patients with autonomic failure or neuropathy.
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