Presence of the aldehyde dehydrogenase 2 variant ALDH2*2 considerably increases EC 50 of nitroglycerin
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LETTER TO THE EDITOR
Presence of the aldehyde dehydrogenase 2 variant ALDH2*2 considerably increases EC50 of nitroglycerin Kentaro Ushijima 1,2
&
Chika Ogami 3 & Yasuhiro Tsuji 4 & Tatsuya Nagano 1,5 & Akio Fujimura 1
Received: 13 August 2020 / Accepted: 14 September 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Large interindividual variability in the vasodilatory effect of nitroglycerin might partly depend on the gene polymorphisminduced alterations in the pharmacokinetics and/or sensitivity of the drug [1, 2]. We have previously observed that aldehyde dehydrogenase 2 (ALDH2) gene polymorphism decreases the vasodilatory effect of nitroglycerin (GTN) in infants [3]. Here, we performed additional analysis concerning ALDH2 gene polymorphism and haemodynamics of GTN. The published data [3] [plasma GTN concentration, pulmonary vascular resistance (PVR) and ALDH2 genotype (Glu504Lys), an allele of ALDH2*2] were used for the analysis. Changes of PVR after GTN dosing (ΔPVR) were analyzed using nonlinear regression based on a direct effect Emax model to describe the relationship between the haemodynamic effect of GTN and its concentration (Eq. 1). ΔPVR ¼ Emax C=ðEC50 þ CÞ
ð1Þ
ΔPVR is a change from baseline PVR in each patient, and C is GTN concentration at a corresponding time. Emax is the GTN concentration estimated to achieve a maximum decrease of PVR, and EC50 is the GTN concentration required to * Kentaro Ushijima [email protected] 1
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, Tochigi 329-0498, Japan
2
Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi, Japan
3
Department of Medical Pharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
4
School of Pharmacy, Nihon University, Chiba, Japan
5
Department of Anesthesiology and Critical Care Medicine, Jichi Medical University, Tochigi, Japan
achieve 50% of Emax. An allele of ALDH2*2 is hypothesized to affect EC50 as described in Eq. 2. ΔPVR ¼ Emax C= EC50 GENE θ þ C ð2Þ (θ = 0, non-carriers; θ = 1, carriers of at least one ALDH2*2 allele.) The nonlinear regression analysis was performed using the nonlinear least squares function of R software. The relation between the predicted and observed ΔPVR is shown in Fig. 1. Model selection of ΔPVR determined by Akaike’s Information Criterion (AIC) [4] was improved using the information regarding the ALDH2*2 allele [Fig. 1a (without information), AIC: 56.3; Fig. 1b (with information), AIC: 21.6). Compared to the EC50 (mean: 12.5ng/ml) for GTN response in carriers of at least one ALDH2*2 allele, the value was 11.6 times greater in patients with the gene polymorphism. After GTN administration, the drug is transformed to lead to the formation of nitric oxide via a high potency pathway mediated by ALDH2 and a low potency pathway mediated by several enzymes, including glutathione-S-transferase [5]. Previous study suggested that apart from nitri
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