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

From the Department of Clinical and Administrative Sciences, Mercer University Southern School of Pharmacy, Atlanta, Georgia (Dr Hon, Dr Jann); the Center for Clinical Research, Mercer University Southern School of Pharmacy, Atlanta, Georgia (Dr Spratlin, Dr Jann); and the Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York (Dr Jusko).

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 ratio were 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.

Key Words: Corticosteroids • methylprednisolone pharmacodynamics • cortisol suppression • histamine suppression • HNMT polymorphism

Address for reprints: Yuen Yi Hon, PharmD, Clinical Pharmacokinetics Research Laboratory, Clinical Center Pharmacy Department, National Institutes of Health, Bldg #10, Rm 1N-257, MSC-1196, 10 Center Drive, Bethesda, MD 20892-1196.