Uticaj genske varijabilnosti adrenergičkih receptora i citohroma P450 oksidaze na farmakokinetiku i terapijsku efikasnost beta blokatora kod pacijenata sa srčanom insuficijencijom
Докторанд
Nikolić, ValentinaМентор
Pešić, SrđanЧланови комисије
Jevtović-Stoimenov, TatjanaIlić, Stevan
Jović, Zorica
Janković, Slobodan
Метаподаци
Приказ свих података о дисертацијиСажетак
The beta-adrenergic receptor (β-AR) pathway is altered in heart failure. Recent
studies have discovered functionally relevant and common polymorphisms in both β1-AR
and β2-AR. These polymorphisms have been implicated with inconsistent results in the
pathogenesis, clinical presentation, and prognosis of patients with heart failure (HF). In
patients with HF, β-blockers reduce mortality. It’s not known whether the the response to β
blockers in patients with HF could be associated with the genotype of drug-metabolizing
enzymes and/or drug targets.
We investigated the correlation of adrenergic receptor polymorphisms β1Ser49Gly,
β1Arg389Gly and β2Arg16Gly with the risk of HF in Serbian population using a casecontrol
study design. The genotype frequencies were in Hardy-Weinberg equilibrium.
These polymorphisms were analysed by polymerase chain reaction-restriction fragment
length polymorphism in patients with HF and compared with the control group.
We also investigated the impact of 3 functio...nal polymorphisms on survival,
hospitalization and emergency department (ED) visits due to HF in carvedilol- and
bisoprolol-treated HF patients. For these propose, 70 patients were enrolled and followed
up at the HF clinic, and vital status was evaluated using electronic hospital and emergency
department records and a local death certificate database.
The aim of this study was to derive population pharmacokinetic (PK) model for
clearance (CL) of carvedilol and bisoprolol, respectively in adult patients with HF using
non-linear mixedeffect modeling (NONMEM).
Finally, purpose of this study was to determine whether genetic polymorphisms in
CYP2D6 correlated with dose of, or response to, bisoprolol or carvedilol treatment in
patients with HF. Carvedilol and bisoprolol concentrations were quantified and effects on
resting heart rate and blood pressure were analyzed using a multivariable clinical-genetic
analysis.
There were no differences or any trends in the allele and genotype frequencies of
the β1Ser49Gly, β1Arg389Gly and β2Arg16Gly polymorphisms. None of these
polymorphisms were associated with adverse outcomes (hospitalization, ED visits or
mortality). There were significant CYP2D6 allele-specific differences in carvedilol
pharmacokinetics, but the CYP2D6 genotype had no effect on heart rate and blood pressure.
Our population pharmacokinetic (PPK) model for the clearance of carvedilol in routinely
treated adult patients with CHF showed that the total body weight, concomitant therapy
with digoxin and smoking tobacco were the main subjects of carvedilol pharmacokinetic
variability. Finally, PPK model for the clearance of bisoprolol showed that the total daily
dose of bisoprolol was the only important covariate.
In conclution, β-blockers are the drugs where CYP2D6-related pharmacokinetic
variation is apparently not carried forward into pharmacodynamic variation. Although
current knowledge does not allow utilizing β1-AR and β2-AR genotypes for clinical
treatment decisions, our data should stimulate further research on the impact of these
genotypes in health and disease.