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 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.

Figure 1

Plasma cortisol concentration versus time profiles for subjects with C/C (top panel) and C/T genotypes (bottom panel). Symbols represent observed data and lines represent fitted curves obtained by Fourier analysis and the pharmacodynamic model shown at the top. The baseline phase is displayed by closed circles and dotted lines. The methylprednisolone phase is depicted by open circles and solid lines.

Figure 2

Whole blood histamine concentration versus time profiles for subjects with C/C (top panel) and C/T genotypes (bottom panel). Symbols represent observed data and lines represent fitted curves. The baseline phase is displayed by closed circles and dotted lines. The methylprednisolone phase is depicted by open circles and solid lines.

Figure 3

Mean (±SD) plasma methylprednisolone concentration versus time curves for subjects who are homozygous (C/C, closed circles) and heterozygous (C/T, open circles) for the wild-type C314 allele.

Figure 4

Mean (±SD) plasma cortisol concentrations after the administration of methylprednisolone for subjects who are homozygous (C/C) and heterozygous (C/T) for the wild-type C314 allele.

Figure 5

Methylprednisolone concentrations causing 50% inhibition of the suppression of cortisol circadian secretion (IC₅₀) and nadir cortisol concentrations between subjects with C/C and C/T genotypes. Horizontal lines show median values.