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Altered Methylprednisolone Pharmacodynamics in Healthy Subjects With Histamine N‐Methyltransferase C314T Genetic Polymorphism
Author(s) -
Hon Yuen Yi,
Jusko William J.,
Spratlin Vicky E.,
Jann Michael W.
Publication year - 2006
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270006286434
Subject(s) - pharmacodynamics , methylprednisolone , histamine , medicine , genotype , endocrinology , glucocorticoid , hydrocortisone , pharmacokinetics , biology , biochemistry , gene
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.