Altered Methylprednisolone Pharmacodynamics in Healthy Subjects With Histamine N‐Methyltransferase C314T Genetic Polymorphism

Abstract

This study investigated the potential differences in methylprednisolone pharmacodynamics between healthy subjects with different histamine N-methyltransferase (HNMT) C314T genotypes. Six individuals with C/C genotype and 4 with C/T genotype were administered a single intravenous dose of methylprednisolone 0.6 mg/kg ideal body weight in a randomized 2-period manner. Methylprednisolone plasma concentrations were fitted with a 1-compartment model. Cortisol and whole blood histamine suppression were assessed by indirect response models, with circadian baseline cortisol analyzed by Fourier analysis. The area between the baseline and effect curve and the area under the effect versus time curve suppression ratiowere used to characterize plasma histamine suppression. Methylprednisolone pharmacokinetics and plasma and whole blood histamine suppression were similar between the 2 genotype groups. Median nadir of cortisol and the 50% inhibitory concentration for cortisol were significantly higher in subjects with C/T genotype than those with C/C genotype (P = .031 and .033, respectively, Wilcoxon rank sum test). Subjects who are heterozygous for the T314 variant allele thus appeared less sensitive to the suppressive effects of methylprednisolone on cortisol secretion. KeywordsCorticosteroids; methylprednisolone pharmacodynamics; cortisol suppression; histamine suppression; HNMT polymorphism Histamine is an important mediator in the body that is involved in the regulation of numerous physiologic and pathophysiologic processes including gastric acid secretion, central nervous system functioning, bronchial asthma, and hypersensitivity reactions. It is formed by decarboxylation of histidine, a metabolic pathway that is catalyzed by histidine NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript decarboxylase (HDC) 1 and is metabolized by diamine oxidase and histamine Nmethyltransferase (HNMT). 2 Histamine N-methyltransferase catalyzes the N-methylation of histamine, which was suggested to be the major significant pathway for the biotransformation of histamine in bronchial epithelium and the brain. [3][4][5] Interindividual variation of HNMT activity has been demonstrated in whites and Han Chinese. 6,7 This variability can be explained in part by a C to T transition at nucleotide 314 (exon 4) of the HNMT gene, causing an amino acid change of threonine to isoleucine at codon 115, which results in low immunoreactive HNMT protein and activity. 8 Previously, HNMT activity in red blood cell lysate was found to be lower in persons who are heterozygous for the T314 allele than in those with homozygous wild-type genotype. 7,8 Corticosteroids are widely used for their anti-inflammatory and immunosuppressive effects in various diseases including allergic diseases such as asthma, urticaria, rhinitis, and anaphylaxis. These agents elicit a number of pharmacodynamic responses including suppression of cortisol secretion, cell trafficking, and whole blood histamine (WBH) concentrations. The suppressive effects of c...

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“…Because subjects with HNMT C314T polymorphism tended to be less sensitive to the suppressive effects of methylprednisolone on cortisol secretion and because this subject has a wild-type HNMT genotype, 20 pharmacodynamic parameter values for cortisol suppression were compared only to 3 control subjects who have the same HNMT genotype. Whereas most of the pharmacodynamic parameters were not apparently different, the concentration causing 50% inhibition (IC 50 ) for whole blood histamine suppression was lower for the study participant than that for the control subjects.…”

“…20 Ten subjects participated and completed the study. We found that 1 subject had distinctly low methylprednisolone clearance, which approximated a 43% decrease compared to that of other subjects.…”

“…20 In brief, methylprednisolone plasma concentrations were fitted with one compartment model. Cortisol and whole blood histamine suppression were assessed by indirect response models, with baseline cortisol analyzed by Fourier analysis.…”

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