Pharmacogenetics may explain part of the interindividual variability of dobutamine pharmacodynamics in neonates

Aims To determine whether the known single nucleotide polymorphisms in adrenoreceptor associated genes affect the haemodynamic response to dobutamine in critically ill neonates. Methods Alleles in the known genetic single nucleotide polymorphisms in beta 1- and beta 2-adrenoceptor (AR) genes and Gs protein alpha-subunit gene (GNAS) possibly affecting inotropic effect were identified in patients of neonatal dobutamine pharmacokinetic-pharmacodynamic study. Linear mixed-effect models were used to describe the effect of genetic polymorphisms to heart rate (HR), left ventricular output (LVO) and right ventricular output (RVO) during dobutamine treatment. Results Twenty-six neonates (5 term, 21 preterm) were studied. Dobutamine plasma concentration and exposure time respective HR (adjusted to gestational age) is dependent on beta 1-AR Arg389Gly polymorphism so that in G/G (Gly) homozygotes and G/C heterozygotes dobutamine increases HR more than in C/C (Arg) homozygotes, with parameter estimate (95% CI) of 38.3 (15.8-60.7) beats/min per AUC of 100 mu g L-1 h, P = .0008. LVO (adjusted to antenatal glucocorticoid administration and illness severity) and RVO (adjusted to gestational age and illness severity) is dependent on GNAS c.393C > T polymorphism so that in T/T homozygotes and C/T heterozygotes but not in C/C homozygotes LVO and RVO increase with dobutamine treatment, 24.5 (6.2-42.9) mL kg(-1) min(-1) per AUC of 100 mu g L-1 h, P = .0095 and 33.2 (12.1-54.3) mL kg(-1) min(-1) per AUC of 100 mu g L-1 h, P = .0025, respectively. Conclusion In critically ill neonates, beta 1-AR Arg389Gly and GNAS c.393C > T polymorphisms may play a role in the haemodynamic response to dobutamine during the first hours and days of life.

Automated summary

The study found that β1-AR Arg389Gly and GNAS c.393C > T polymorphisms may affect the haemodynamic response to dobutamine in critically ill neonates.