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

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.

Single and multiple dose pharmacokinetics of a novel mirtazapine transdermal ointment in cats.

Single and multiple dose pharmacokinetics (PK) of mirtazapine transdermal ointment applied to the inner ear pinna of cats were assessed. Study 1 was a randomized, cross-over single dose study (n = 8). Cats were treated once with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner ear pinna (treatment) or administered orally (control) and then crossed over after washout. Plasma was collected predose and at specified intervals over 96 hr following dosing. Study 2 was a multiple dose study (n = 8). Cats were treated daily for 14 days with 0.5 mg/kg of mirtazapine transdermal ointment applied topically to the inner pinna. Plasma was collected on Day 13 predose and at specified intervals over 96 hr following the final dose. In Study 1, single transdermal administration of mirtazapine resulted in mean Tmax = 15.9 hr, Cmax = 21.5 ng/mL, AUC0-24 = 100 ng*hr/mL, AUC0-∞ = 260 ng*hr/mL and calculated half-life = 26.8 hr. Single oral administration of mirtazapine resulted in mean Tmax = 1.1 hr, Cmax = 83.1 ng/mL, AUC0-24 = 377 ng*hr/mL, AUC0-∞ = 434 ng*hr/mL and calculated half-life = 10.1 hr. Mean relative bioavailability (F) of transdermal to oral dosing was 64.9%. In Study 2, daily application of mirtazapine for 14 days resulted in mean Tmax = 2.1 hr, Cmax = 39.6 ng/mL, AUC0-24 = 400 ng*hr/mL, AUC0-∞ = 647 ng*hr/mL and calculated half-life = 20.7 hr. Single and repeat topical doses of a novel mirtazapine transdermal ointment achieve measurable plasma concentrations in cats.

Long-term stability of five atypical antipsychotics (risperidone, olanzapine, paliperidone, clozapine, quetiapine) and the antidepressant mirtazapine in human serum assessed by a validated SPE LC-MS/MS method.

Long-term sample stability of five atypical antipsychoticdrugs risperidone, paliperidone, clozapine, quetiapine and olanzapine and the antidepressant drug mirtazapine in serum was studied by use of a newly developed and validated analytical method based on solid-phase extraction and liquid chromatography-tandem mass spectrometry. Ascorbic acid was used as an antioxidative agent to stabilize olanzapine during storage and sample preparation. We assessed analyte stability on long-term storage in serum samples at 25°C, 5°C, -20°C and -80°C, and during five freeze-thaw cycles. Analytes were stable for 23 days at room temperature except for olanzapine and mirtazapine (17 days). All analytes were stable for at least 30 days at 5°C. All analytes were stable for 270 days at -20°C, except for paliperidone and mirtazapine with 60 days and 180 days, respectively. All analytes were stable for 270 days at -80°C. Furthermore, all analytes were stable for five freeze-thaw cycles. We recommend storage at -80°C when samples drawn for analysis of antipsychotic drugs are stored for more than 60 days, whereas a temperature of -20°C is sufficient for storage less than 60 days.

High blood mirtazapine concentration in a newborn - A case of suspected postpartum infanticide.

We report a sudden death of an infant due to mirtazapine poisoning. A 15-day-old newborn boy was found dead when he was sleeping beside his mother who had suffered from panic disorder for approximately 1 year. After giving birth, she complained of palpitations and shaky hands, and was prescribed mirtazapine. The deceased newborn weighed 3,282 g and his height was 55 cm. There were no autopsy findings related to the death. The mirtazapine concentration as quantitated by liquid chromatography-tandem mass spectrometry analysis was 620 ng/mL in right heart blood, and was approximately 10 times higher than the therapeutic level in adults. Because transfer of mirtazapine into breast milk is low, mirtazapine was likely administered intentionally to the newborn. Based on the newborn's immature renal, liver, and blood-brain barrier function, the cause of death was attributed to mirtazapine poisoning. Poison-related homicide in the infant is rare. We report the first case of intentional mirtazapine poisoning case in a newborn.

The Association of CYP2D6*4 and POR*28 Polymorphisms on Mirtazapine Plasma Level in Subjects with Major Depressive Disorder and Anxiety Disorders.

AIMS AND OBJECTIVE: The plasma level of mirtazapine (MIR) varies between individuals primarily depending on the differences in metabolism during pharmacotherapy. CYP2D6 takes the role as a major enzyme in MIR metabolism and POR enzyme donates an electron to CYP2D6 for its activity. Single nucleotide polymorphisms in the genes encoding pharmacokinetic enzymes may cause changes in enzyme activity, leading to differences in metabolism of the drug. Our aim was to assess the influence of CYP2D6*4 and POR*28 polymorphisms on MIR plasma levels in Turkish psychiatric patients. MATERIALS AND METHODS: The association between genetic variations and plasma level of MIR was investigated on 54 patients. CYP2D6*4 and POR*28 polymorphisms were analysed using Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) and plasma MIR levels were measured using HPLC. RESULTS: Allele frequencies of CYP2D6*4 and POR*28 were 0.11 and 0.39, respectively in the study population. The results showed that CYP2D6*4 allele carriers have higher C/D MIR levels while POR*28 allele carriers have lower C/D MIR levels. Combined genotype analyses also revealed that individuals with CYP2D6*1/*1 - POR*28/*28 genotype have a statistically lower C/D MIR level (0.95 ng/ml/dose) when compared with individuals with CYP2D6*1/*1 - POR*1/*1 genotype (1.52 ng/ml/dose). CONCLUSION: Our results indicate that CYP2D6*4 and POR*28 polymorphisms may have a potential in the explanation of differences in plasma levels in MIR treated psychiatric patients. A combination of these variations may be beneficial in increasing drug response and decreasing adverse drug reactions in MIR psychopharmacotherapy.

Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of alternative pathways apart from CYP1A2.

Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.

In vivo and in vitro assessment of mirtazapine pharmacokinetics in cats with liver disease.

BACKGROUND: Liver disease (LD) prolongs mirtazapine half-life in humans, but it is unknown if this occurs in cats with LD and healthy cats. HYPOTHESIS/OBJECTIVES: To determine pharmacokinetics of administered orally mirtazapine in vivo and in vitro (liver microsomes) in cats with LD and healthy cats. ANIMALS: Eleven LD and 11 age-matched control cats. METHODS: Case-control study. Serum was obtained 1 and 4 hours (22 cats) and 24 hours (14 cats) after oral administration of 1.88 mg mirtazapine. Mirtazapine concentrations were measured by liquid chromatography with tandem mass spectrometry. Drug exposure and half-life were predicted using limited sampling modeling and estimated using noncompartmental methods. in vitro mirtazapine pharmacokinetics were assessed using liver microsomes from 3 LD cats and 4 cats without LD. RESULTS: There was a significant difference in time to maximum serum concentration between LD cats and control cats (median [range]: 4 [1-4] hours versus 1 [1-4] hours; P = .03). The calculated half-life of LD cats was significantly prolonged compared to controls (median [range]: 13.8 [7.9-61.4] hours versus 7.4 [6.7-9.1] hours; P < .002). Mirtazapine half-life was correlated with ALT (P = .002; r = .76), ALP (P < .0001; r = .89), and total bilirubin (P = .0008; r = .81). The rate of loss of mirtazapine was significantly different between microsomes of LD cats (-0.0022 min-1 , CI: -0.0050 to 0.00054 min-1 ) and cats without LD (0.01849 min-1 , CI: -0.025 to -0.012 min-1 ; P = .002). CONCLUSIONS AND CLINICAL IMPORTANCE: Cats with LD might require less frequent administration of mirtazapine than normal cats.