Makmor Bakry, Mohd
Influence of genetic variability on the clinical pharmacology of carbamazepine and lamotrigine.
PhD thesis, University of Glasgow.
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This research programme investigates the influence of genetic variability on the clinical pharmacology of carbamazepine (CBZ) and lamotrigine (LTG).
Common polymorphisms in genes that may influence the response to CBZ and LTG include CYP3A4 g.-392A>G, CYP3A5 g.6986A>G, CYP1A2 g.5734C>A, EPHX1 c.337T>C, EPHX1 c.416A>G, UGT2B7 c.802C>T, ABCB1 c.1236C>T, ABCB1 c.2677G>T/A, ABCB1 c.3435C>T and SCN2A c.56G>A.
The prevalence of these common polymorphisms was evaluated in a 400-strong study population from a single research unit. Minor allele frequency ranged between 3.5% (CYP3A4 -392G) and 48.0% (ABCB1 1236T). Allele and genotype distributions were comparable to published data for other Caucasian populations.
The influence of common polymorphisms in drug metabolising enzyme (DME) and sodium channel genes on the optimal dose of CBZ was assessed in a cohort of 70 patients. This study revealed that age and common polymorphisms in the EPHX1 gene (c.337T>C and c.416A>G) are potential predictors for optimal dose of CBZ. The significant effects of EPHX1 variants may be explained by their significant contribution to the inactivation of CBZ. These potential predictors explain approximately 15% of the inter-individual variation in CBZ dose requirements.
Preliminary findings suggest that common polymorphisms in DME genes do not form a unique profile which increases the risk of developing intolerable CBZ adverse effects.
It is unlikely that common polymorphisms in ABCB1 and SCN2A genes influence the expression and/or activity of their respective proteins to the level at which they can dictate response to LTG therapy.
The influence of common polymorphisms in ABCB1 and SCN2A genes on the optimal dose of LTG was assessed in a cohort of 94 patients. Optimal dose in this study was defined as the final dose given to the patients that successfully maintained seizure freedom for at least 1 year with LTG monotherapy. Several basic clinical factors such as age and gender were also examined as potential predictors. The effect of predictors on the optimal dose of LTG was investigated using linear regression analysis. This study revealed that gender and common polymorphisms in the ABCB1 gene (c.1236C>T and c.3435C>T) are potential predictors for optimal dose of LTG. These predictors explain approximately 17% of the inter-individual variation in LTG dose requirement. These findings further highlight the potential role of P-gp in the management of epilepsy.
The final study investigated the influence of ABCB1 c.1236C>T and ABCB1 c.3435C>T polymorphisms on the pharmacokinetics of LTG. A total of 156 blood samples from 50 patients receiving LTG monotherapy were available for analysis. The influence of ABCB1 variants was evaluated by population pharmacokinetics. This approach successfully estimated the oral clearance of LTG monotherapy at steady-state. However, the absorption rate constant (Ka) and volume of distribution (Vd) of LTG were poorly estimated. The inclusion of common polymorphisms in the ABCB1 gene in the pharmacokinetic model did not improve the estimation of oral clearance. This may indicate that common variants of ABCB1 do not influence clearance of LTG.
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