Nothing titillating for this post. Just a new PNAS paper that provides a nice example of pharmacogenetics: Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.
David Goldstein’s group at University College London have identified genetic variations associated with dose response to two anti-epileptic drugs (AEDs): phenytoin and carbamazepine. A broad range of doses are used with these drugs, and the final “maintenance” dose for each patient is normally determined by trial and error.
In this paper, they report that a known functional polymorphism in the CYP2C9 gene is highly associated with the maximum dose of phenytoin (P = 0.0066). They also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively).
How does a polymorphism in an intron affect drug metabolism?
This polymorphism disrupts the consensus sequence of the 5′ splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy.
If their findings are corroborated, genotyping could be used by doctors to more quickly determine the proper maintenance dose for these drugs.
Here are some fun parts from their discussion:
We have associated functional polymorphisms with the dose used in regular clinical practice for two leading AEDs, phenytoin and carbamazepine. For phenytoin, a well known low-activity variant in the CYP2C9 gene associates with dose, as does a functional variant in the SCN1A gene, encoding the target of phenytoin. The SCN1A variant is also highly associated with dosing of carbamazepine, thus providing functional replication of the effect of this variant. This functional replication, together with the apparent function of this polymorphism, makes a strong case that the association reported here is real. However, although the case made here is compelling, as is usual with association genetics, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication. To our knowledge, this SCN1A variant is the first polymorphism in a drug target associated with the use of an AED and one of only a handful of target polymorphisms for which there is strong evidence of an effect on clinical drug use (22). Furthermore, our study demonstrates the pharmacologic significance of alternative splicing in a human sodium channel. Although there are other examples of alternative splicing in other human sodium channel genes, none has been associated with functional effects (23).
This polymorphism is potentially of more general importance because of the prominence of sodium channel blockade in the treatment of epilepsy (and other neurological conditions). For example, more than half of epilepsy patients treated pharmacologically in the United Kingdom receive a drug that principally targets the sodium channel (24).
Concluding:
Our results support the view that the major target, transporter, and drug metabolizing enzyme are good starting points to study drug response and that pharmacogenetic traits, therefore, are more tractable for genetic analyses than are those for common disease predisposition (22). We also emphasize that a haplotypetagging strategy (14) identified a previously unknown functional variant in the SCN1A gene. This functional variant was found 91 bp away from the nearest exon known at the time of the study, illustrating the need for exhaustive tagging.
Overall, our findings suggest that using genotype data may make it possible to safely reduce the time required to reach an effective dose. Therefore, it is also a priority to assess the utility of dose adjustment on the basis of genotype for these medicines in a prospective clinical study. Prospective studies of carbamazepine and phenytoin, informed by a detailed retrospective study, would also serve as a useful model for future pharmacogenetic studies (25).
Posted by rikurzhen at 12:06 AM