Background: Presurgical treatment with an alpha-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced alpha-adrenergic receptor mediated vasoconstriction in patients... Show moreBackground: Presurgical treatment with an alpha-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced alpha-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in alpha-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the alpha 1A, alpha 1B, alpha 1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and alpha 2A, alpha 2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of alpha-adrenergic receptor blocker (p < 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of alpha-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to alpha-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations. Show less
Bins, S.; Huitema, A.D.R.; Laven, P.; Bouazzaoui, S. el; Yu, H.X.; Erp, N. van; ... ; Koolen, S.L.W. 2019
Background and ObjectiveAs pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib... Show moreBackground and ObjectiveAs pazopanib plasma trough concentrations are correlated with treatment outcome, we explored whether single nucleotide polymorphisms in the elimination pathway of pazopanib affect systemic pazopanib concentrations.MethodsThe decreased function alleles CYP3A4 15389 C>T (*22), ABCB1 3435 C>T, ABCG2 421 C>A, and ABCG2 34G>A were analyzed within a recently developed population-pharmacokinetic model.ResultsIncorporation of CYP3A4*22 in the model resulted in a 35% lower clearance for variant carriers (0.18 vs. 0.27 L/h; difference in objective function value: -9.7; p<0.005). Simulated median trough concentrations of cancer patients with CYP3A4*22 with 600mg once daily or 800mg once daily were 31 and 35mg/L, respectively. The simulated trough concentrations for the population excluding the CYP3A4*22 carriers after 600mg once daily or 800mg once daily were 18 and 20mg/L, respectively.ConclusionThis analysis shows that CYP3A4*22 heterozygotes have a substantial lower pazopanib clearance and that dose adjustments based on CYP3A4*22 status could be considered. Show less
