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

2019 ◽  
Vol 52 (05) ◽  
pp. 237-244
Author(s):  
Masataka Shinozaki ◽  
Jason Pierce ◽  
Yuki Hayashi ◽  
Takashi Watanabe ◽  
Taro Sasaki ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Plasma Levels ◽  
High Performance ◽  
Psychiatric Patients ◽  
Plasma Concentrations ◽  
Steady State Concentration ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
State Concentration

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.

scholarly journals Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

1999 ◽  
Vol 43 (5) ◽  
pp. 1152-1155 ◽  
Author(s):  
Kevin W. Garey ◽  
Charles A. Peloquin ◽  
Paul G. Godo ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Steady State Concentration ◽  
Open Label ◽  
Time Curve ◽  
Data Analyses ◽  
Concentration Time ◽  
State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

Quantification of the steady-state plasma concentrations of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia using a novel HPLC method and the effects of CYPs and ABC transporters polymorphisms

2017 ◽  
Vol 54 (6) ◽  
pp. 677-685 ◽  
Author(s):  
Yumiko Akamine ◽  
Yuka Sugawara-Kikuchi ◽  
Tsukasa Uno ◽  
Tetsuo Shimizu ◽  
Masatomo Miura
Keyword(s):  
Steady State ◽  
High Performance ◽  
Plasma Concentrations ◽  
Japanese Patients ◽  
Hplc Method ◽  
Coefficients Of Variation ◽  
Trough Concentrations ◽  
Polymerase Chain ◽  
Cyp 2D6 ◽  
State Plasma

Background This study developed a novel high-performance liquid chromatography (HPLC) method for the simultaneous quantification of clozapine and its active metabolite, N-desmethylclozapine, in human plasma and investigated the effects of various factors, including genetic polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A5, ABCB1 and ABCG2, on the steady-state plasma trough concentrations (C0) of clozapine and N-desmethylclozapine in Japanese patients with schizophrenia. Methods Forty-five patients had been receiving fixed doses of clozapine for at least four weeks. The CYP2D6 ( CYP2D6*2, CYP2D6*5, CYP2D6*10), CYP3A5 ( CYP3A5*3), ABCB1 (1236C > T, 2677G > T/A, 3435C > T) and ABCG2 (421 C > A) genotypes were identified by polymerase chain reaction. Results The within- and between-day coefficients of variation (CV) were less than 11.0%, and accuracy was within 9.0% over the linear range from 10 to 2500 ng/mL for both analytes, and their LOQs were each 10 ng/mL. The median C0/dose (C0/D) ratios of clozapine were significantly higher in patients with the ABCG2 421 A allele than in those with the 421 C/C genotype ( P = 0.010). However, there were no significant differences in C0/D ratios of clozapine and N-desmethylclozapine among ABCB1, CYP2D6 or CYP3A5 genotypes. In multiple regression analysis, including polymorphisms, age, body weight and biochemical data of patients, the ABCG2 polymorphism alone was correlated with the C0/D ratios of clozapine ( R2 = 0.139, P = 0.016). Conclusions Among the various CYPs and drug transporters, BCRP appeared to most strongly influence clozapine exposure. Knowledge of the patient’s ABCG2 421 C > A genotype before initiating therapy may be useful when making dosing decisions aimed at achieving optimal clozapine exposure.

Therapeutic Drug Monitoring of Posaconazole in Adult Acute Myeloid Leukemia (Aml) Patients Receiving Posaconazole Prophylaxis during Induction: Experience from a Center with High Invasive Fungal Infection (IFI)Burden

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4005-4005 ◽  
Author(s):  
Manju Sengar ◽  
Sanyo Dsouza ◽  
Raviraj Deshpande ◽  
Hasmukh Jain ◽  
Murari Gurjar ◽  
...  
Keyword(s):  
Steady State ◽  
Therapeutic Drug Monitoring ◽  
Fungal Infection ◽  
Median Time ◽  
Drug Monitoring ◽  
Plasma Levels ◽  
Therapeutic Drug ◽  
Steady State Concentration ◽  
State Concentration ◽  
Trough Levels

Abstract Background: Posaconazole has been recommended as an antifungal of choice for IFI prophylaxis in AML during induction therapy. Very high incidence of possible and probable IFI (70%) during induction at our centre led to adoption of posaconazole prophylaxis. However, approximately 50% of patients still require change of antifungal due to suspected breakthrough IFI raising the possibility of inadequate plasma levels due to various factors (variable absorption, metabolism and drug interactions). To address this concern, we evaluated the role of therapeutic drug monitoring (TDM) in AML patients receiving posaconazole prophylaxis to identify whether suboptimal plasma levels (<700 ng/mL) are associated with breakthrough IFI. Method: This prospective observational study included all patients, 18 years or more, undergoing induction chemotherapy for de novo AML with no evidence of IFI (normal CT chest, and galactomannan assay) and on posaconazole prophylaxis between May2015 to February 2016 at our centre. Posaconazole oral suspension 200 mg three times daily was given for antifungal prophylaxis from day 1 of induction until neutrophil recovery to more than 500 cells/μL, occurrence of a confirmed or suspected IFI or development of drug related toxicity or intolerance. The details regarding demography, weight, BMI at diagnosis were recorded. During therapy all adverse events including vomiting and diarrhea were recorded as per CTCAE version 4.03. Concomitant drug history and use of proton pump inhibitors, antacids, metoclopramide and domperidone during treatment period were noted. Blood samples (7 am) for detecting posaconazole trough levels were collected daily from day 4 till day 12 of induction. If patient developed symptoms and signs suggestive of IFI during induction after day 12, then blood sample was drawn for posaconazole trough levels. Plasma posaconazole levels were estimated at by HPLC method. The diagnosis of IFI was in accordance with the revised European Organization for Research and Treatment of Cancer /Mycoses Study Group definitions published in 2008. Breakthrough invasive fungal infection was also diagnosed if there was failure to respond to intravenous antibiotics along with negative cultures and fever defervescence with change in antifungal therapy. The primary objective of the study was to assess the percentage of patients achieving target posaconazole plasma levels. The secondary objectives included i) impact of achieving target drug concentration in preventing breakthrough fungal infections. ii) identification of factors associated with subtoptimal posaconazole levels. iii) Time to achieve steady state concentration or target trough concentrations of posaconazole. Results: A total of 366 samples were collected from 45 patients with median number of 8 samples (range 1-9) per patient. Median age of patients was 36 years (range 18-45 years). Thirty two were males. Thirty-nine patients received 3+7 regimen and 6 were treated with cladribine along with daunomycin and cytarabine. Eleven patients (24%) did not achieve target plasma levels (≥700 ng/mL) even once till day 12. Median time to achieve steady state concentration was 5 days (range 4-10). At steady state 20 (44% ) patients had suboptimal plasma levels. On serial monitoring, a declining trend in plasma levels was observed after day 8 in 31 patients. Twenty three patients (51%) developed possible/ probable IFI on posaconazole prophylaxis. The median time to develop IFI was 13 days (range 4-24 days). Twenty out of 23 patients (87%) who developed IFI had suboptimal plasma levels as compared to 13 out of 22 patients (60%) who did not develop IFI (p-0.04). In all but 3 patients, the plasma levels declined before breakthrough IFI. On logistic regression analysis, both the steady state concentration and plasma posaconazole levels before breakthrough were strong predictors of occurrence of breakthrough IFI. Presence of mucositis, vomiting, diarrhea, use of antacid was associated with low plasma levels on univariate analysis. On multivariate analysis presence of mucositis and antacids remained significantly associated with low plasma levels. Conclusion: TDM has a role in patients receiving posaconazole prophylaxis, however it still needs to be seen if dose adjustments based on plasma levels can reduce the risk of breakthrough IFI. Disclosures No relevant conflicts of interest to declare.

High performance Nanogold™-in situ hybridzation and its use in the detection of hybridized and PCR-amplified microscopical preparations

1996 ◽  
Vol 54 ◽  
pp. 896-897
Author(s):  
G. W. Hacker ◽  
I. Zehbe ◽  
J. Hainfeld ◽  
A.-H. Graf ◽  
C. Hauser-Kronberger ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Messenger Rna ◽  
High Performance ◽  
Detection System ◽  
Direct Methods ◽  
Genetic Alterations ◽  
Chain Reaction ◽  
Protein Encoding ◽  
Polymerase Chain

In situ hybridization (ISH) with biotin-labeled probes is increasingly used in histology, histopathology and molecular biology, to detect genetic nucleic acid sequences of interest, such as viruses, genetic alterations and peptide-/protein-encoding messenger RNA (mRNA). In situ polymerase chain reaction (PCR) (PCR in situ hybridization = PISH) and the new in situ self-sustained sequence replication-based amplification (3SR) method even allow the detection of single copies of DNA or RNA in cytological and histological material. However, there is a number of considerable problems with the in situ PCR methods available today: False positives due to mis-priming of DNA breakdown products contained in several types of cells causing non-specific incorporation of label in direct methods, and re-diffusion artefacts of amplicons into previously negative cells have been observed. To avoid these problems, super-sensitive ISH procedures can be used, and it is well known that the sensitivity and outcome of these methods partially depend on the detection system used.

scholarly journals Ileal transposition helps to regulate plasma hepatokine levels in obese Zucker (Crl:ZUC(ORL)-Leprfa) rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dominika Stygar ◽  
Tomasz Sawczyn ◽  
Agnieszka Dulska ◽  
Elżbieta Chełmecka ◽  
Łukasz Mielańczyk ◽  
...  
Keyword(s):  
Body Weight ◽  
Plasma Levels ◽  
Plasma Concentrations ◽  
The Body ◽  
Retinol Binding Protein ◽  
Fibroblast Growth Factor 21 ◽  
Adult Males ◽  
Total Lipids ◽  
Ileal Transposition ◽  
Sham Surgery

AbstractWe studied the long-term effect of ileal transposition (IT) metabolic surgery on the hepatokines: retinol-binding protein-4 (RBP4), α-2-HS-glycoprotein (aHSG/fetuin-A), and fibroblast growth factor 21 (FGF21), C-reactive protein (CRP) plasma levels, glucose metabolism, body weight, liver histology, as well as total lipids concentration in muscle, liver, and fat tissue of obese Zucker (Crl:ZUC(ORL)-Leprfa) rats. 14 adult males were randomly submitted either to IT or SHAM (control) surgery. Pre-operative hepatokines plasma levels were not significantly different in rats submitted to IT or SHAM protocol. Three months after the procedures the plasma levels of RBP4, aHSG, FGF21, and CRP were significantly lower in IT-operated animals when compared to SHAM-operated group. Three and 12 weeks after the IT and SHAM surgery, the AUCOGTT were significantly lower than AUCOGTT before the surgery. HOMA-IR was lower in rats after IT surgery in comparison to the SHAM-operated rats. Muscle and liver total lipids concentration was reduced after the IT procedure when compared to pre-IT conditions. IT had a significant reductive impact on the body weight in comparison to SHAM surgery in the 4th, 6th, 8th, and 10th week after the surgery. We conclude that IT reduces hepatokines’ plasma concentrations, muscle and liver total lipids concentration but not the inflammatory processes in the liver of Zucker (Crl:ZUC(ORL)-Leprfa) rats.

Divergent effects of intravenous GSH and cysteine on renal and hepatic GSH

1992 ◽  
Vol 263 (2) ◽  
pp. R348-R352 ◽  
Author(s):  
S. Aebi ◽  
B. H. Lauterburg
Keyword(s):  
Steady State ◽  
De Novo ◽  
Feedback Inhibition ◽  
Therapeutic Use ◽  
Steady State Concentration ◽  
De Novo Synthesis ◽  
State Concentration ◽  
Cellular Thiol

There is a growing interest in the therapeutic use of sulfhydryls. To assess the effect of glutathione (GSH) and cysteine on the cellular thiol status, thiols were administered intravenously to rats in doses ranging from 1.67 to 8.35 mmol/kg with and without pretreatment with 4 mmol/kg buthionine-[S,R]-sulfoximine (BSO), an inhibitor of GSH synthesis. One hour after administration of 1.67 mmol/kg GSH, the concentration of GSH rose from 5.2 +/- 1.0 to 8.4 +/- 0.9 mumol/g and from 2.5 +/- 0.5 to 3.7 +/- 0.7 mumol/g in liver and kidneys, respectively. After 8.35 mmol/kg, hepatic GSH did not increase further, but renal GSH rose to 6.7 +/- 1.8 mumol/g. Infusion of cysteine increased hepatic GSH to the same extent as intravenous GSH, but renal GSH did not increase after 1.67 mmol/kg and even significantly decreased to 0.6 +/- 0.2 mumol/g after 8.35 mmol/kg. In the presence of BSO, GSH resulted in a significant increase in renal but not hepatic GSH, suggesting that the kidneys take up intact GSH and indicating that the increment in hepatic GSH was due to de novo synthesis. The present data show that hepatic GSH can be markedly increased in vivo by increasing the supply of cysteine. Measurements of hepatic cysteine indicate that up to a concentration of approximately 0.5 mumol/g cysteine is a key determinant of hepatic GSH, such that the physiological steady-state concentration of GSH in the liver appears to be mainly determined by the availability of cysteine. At higher concentrations GSH does not increase further, possibly due to feedback inhibition of GSH synthesis or increased efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

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