8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine

Abstract

Introduction  To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G).

Methods  Seventy-nine Japanese psychiatric patients were treated with MIR for 1–8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes.

Results  Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight–corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight–corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles.

Discussion  The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

Key words

mirtazapine - hydroxylation - glucuronidation - pharmacokinetics - pharmacogenetics

• References

• 1 Hiemke C, Bergemann N, Clement HW. et al. Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018; 51: 9-62
• 2 De Boer T, Nefkens F, Van Helvoirt A. The alpha 2-adrenoceptor antagonist Org 3770 enhances serotonin transmission in vivo. Eur J Pharmacol 1994; 253: R5-R6
• 3 de Boer TH, Nefkens F, van Helvoirt A. et al. Differences in modulation of noradrenergic and serotonergic transmission by the alpha-2 adrenoceptor antagonists, mirtazapine, mianserin and idazoxan. J Pharmacol Exp Ther 1996; 277: 852-860
• 4 Kent JM. SNaRIs, NaSSAs, and NaRIs: New agents for the treatment of depression. Lancet 2000; 355: 911-918
• 5 de Boer T. The effects of mirtazapine on central noradrenergic and serotonergic neurotransmission. Int Clin Psychopharmacol 1995; 10 Suppl 4 19-23
• 6 de Graaf JS, Delbressine LPC. Contributions of the enantiomers of mirtazapine (Org 3770) and of its demethyl metabolite to its neuropharmacological profile in rats. Eur J Pharmacol 1990; 183: 583-584
• 7 Timmer CJ, Sitsen JM, Delbressine LP. Clinical pharmacokinetics of mirtazapine. Clin Pharmacokinet 2000; 38: 461-474
• 8 Okubo M, Murayama N, Miura J. et al. Effects of cytochrome P450 2D6 and 3A5 genotypes and possible coadministered medicines on the metabolic clearance of antidepressant mirtazapine in Japanese patients. Biochem Pharmacol 2015; 93: 104-109
• 9 Delbressine LP, Moonen ME, Kaspersen FM. et al. Pharmacokinetics and biotransformation of mirtazapine in human volunteers. Clin Drug Investig 1998; 15: 45-55
• 10 Jaquenoud Sirot E, Harenberg S, Vandel P. et al. Multicenter study on the clinical effectiveness, pharmacokinetics, and pharmacogenetics of mirtazapine in depression. J Clin Psychopharmacol 2012; 32: 622-629
• 11 Dodd S, Boulton DW, Burrows GD. et al. In vitro metabolism of mirtazapine enantiomers by human cytochrome P450 enzymes. Hum Psychopharmacol 2001; 16: 541-544
• 12 Watanabe T, Hayashi Y, Aoki A. et al. Impact of CYP2D6*10 polymorphism on the pharmacokinetics of mirtazapine and its desmethylated metabokite in Japanese psychiatric patients treated with mirtazapine. Clin Neuropsychopharmacol Ther 2015; 6: 5-15
• 13 Quimby JM, Gustafson DL, Samber BJ. et al. Studies on the pharmacokinetics and pharmacodynamics of mirtazapine in healthy young cats. J Vet Pharmacol Ther 2011; 34: 388-396
• 14 Hayashi Y, Watanabe T, Aoki A. et al. Factors affecting steady-state plasma concentrations of enantiomeric mirtazapine and its desmethylated metabolites in Japanese psychiatric patients. Pharmacopsychiatry 2015; 48: 279-285
• 15 Paus E, Jonzier-Perey M, Cochard N. et al. Chirality in the new generation of antidepressants: Stereoselective analysis of the enantiomers of mirtazapine, N-demethylmirtazapine, and 8-hydroxymirtazapine by LC-MS. Ther Drug Monit 2004; 26: 366-374
• 16 Johansson I, Oscarson M, Yue QY. et al. Genetic analysis of the Chinese cytochrome P4502D locus: characterization of variant CYP2D6 genes present in subjects with diminished capacity for debrisoquine hydroxylation. Mol Pharmacol 1994; 46: 452-459
• 17 Steen VM, Andreassen OA, Daly AK. et al. Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. Pharmacogenetics 1995; 5: 215-223
• 18 Cohen M, Panagides J, Timmer CJ. et al. Pharmacokinetics of mirtazapine from orally administered tablets: Influence of a high-fat meal. Eur J Drug Metab Pharmacokinet 1997; 22: 103-110
• 19 Shams M, Hiemke C, Hartter S. Therapeutic drug monitoring of the antidepressant mirtazapine and its N-demethylated metabolite in human serum. Ther Drug Monit 2004; 26: 78-84
• 20 Meineke I, Steinmetz H, Kirchheiner J. et al. Therapeutic drug monitoring of mirtazapine, desmethylmirtazapine, 8-hydroxymirtazapine, and mirtazapine-N-oxide by enantioselective HPLC with fluorescence detection. Ther Drug Monit 2006; 28: 760-765
• 21 Berling I, Isbister GK. Mirtazapine overdose is unlikely to cause major toxicity. Clin Toxicol (Phila) 2014; 52: 20-24
• 22 Borobia AM, Novalbos J, Guerra-Lopez P. et al. Influence of sex and CYP2D6 genotype on mirtazapine disposition, evaluated in Spanish healthy volunteers. Pharmacol Res 2009; 59: 393-398
• 23 Lind AB, Reis M, Bengtsson F. et al. Steady-state concentrations of mirtazapine, N-desmethylmirtazapine, 8-hydroxymirtazapine and their enantiomers in relation to cytochrome P450 2D6 genotype, age and smoking behaviour. Clin Pharmacokinet 2009; 48: 63-70
• 24 Shimoda K, Noguchi T, Ozeki Y. et al. Metabolism of clomipramine in a Japanese psychiatric population: hydroxylation, desmethylation, and glucuronidation. Neuropsychopharmacology 1995; 12: 323-333
• 25 Someya T, Shibasaki M, Noguchi T. et al. Haloperidol metabolism in psychiatric patients: importance of glucuronidation and carbonyl reduction. J Clin Psychopharmacol 1992; 12: 169-174