Hepatic enzyme induction patterns and phenothiazine side effects

Wright, Jesse H.; Whitaker, S.; Welch, Cynthia B; Teller, David N.

doi:10.1038/clpt.1983.210

Cited by 5 publications

(1 citation statement)

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“…Glucaric acid is of interest since it also relates to sorbitol and gluconic acid, being only a single oxidation step away from gluconic acid. Glucaric acid has been frequently monitored in urine as a marker of xenobiotic stress and urinary levels have been observed to rise in response to treatments with phenothiazines (such as the antipsychotic, chlorpromazine) [54] . Sedoheptulose is considerably elevated in SDB brains while a compound putatively identified as deoxysedoheptulose phosphate is depressed.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls

Zhang

Ali

et al. 2016

Computational and Structural Biotechnology Journal

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Metabolomic profiling was carried out on 53 post-mortem brain samples from subjects diagnosed with schizophrenia, depression, bipolar disorder (SDB), diabetes, and controls. Chromatography on a ZICpHILIC column was used with detection by Orbitrap mass spectrometry. Data extraction was carried out with m/z Mine 2.14 with metabolite searching against an in-house database. There was no clear discrimination between the controls and the SDB samples on the basis of a principal components analysis (PCA) model of 755 identified or putatively identified metabolites. Orthogonal partial least square discriminant analysis (OPLSDA) produced clear separation between 17 of the controls and 19 of the SDB samples (R2CUM 0.976, Q2 0.671, p-value of the cross-validated ANOVA score 0.0024). The most important metabolites producing discrimination were the lipophilic amino acids leucine/isoleucine, proline, methionine, phenylalanine, and tyrosine; the neurotransmitters GABA and NAAG and sugar metabolites sorbitol, gluconic acid, xylitol, ribitol, arabinotol, and erythritol. Eight samples from diabetic brains were analysed, six of which grouped with the SDB samples without compromising the model (R2 CUM 0.850, Q2 CUM 0.534, p-value for cross-validated ANOVA score 0.00087). There appears on the basis of this small sample set to be some commonality between metabolic perturbations resulting from diabetes and from SDB.

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Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls

Zhang

Ali

et al. 2016

Computational and Structural Biotechnology Journal

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Enzyme Induction by Moricizine: Time Course and Extent in Healthy Subjects

Benedek

Davidson

Pieniaszek

1994

The Journal of Clinical Pharma

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Moricizine.HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.

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Glucuronidation enzymes, genes and psychiatry

Leon

2003

Int. J. Neuropsychopharm.

102

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The phase I cytochrome P450 (CYP) isoenzymes have received substantial attention in the pharmacogenetic literature. Researchers are beginning to examine the role of the phase II UDP-glucuronosyltransferase (UGT) enzymes, which produce products that are more water-soluble, less toxic and more readily excreted than the parent compounds. Several reasons may have contributed to neglect of UGTs (compared to CYPs) including: (1) the overlapping activity of UGTs and lack of selective probes; (2) the complexity of the glucuronidation cycle; and (3) the difficulty in developing analytic methods to measure glucuronides. Current CYP knowledge is used as a model to predict advances in UGT knowledge. At least 24 different UGT human genes have been identified and are classified in two families (UGT1 and UGT2) based on sequence homology. The UGT1A subfamily (genes located on chromosome 2) glucuronidates bilirubin, thyroid hormones, and some medications. UGT1A4 metabolizes tricyclic antidepressants and some antipsychotics. The UGT2B subfamily (genes located on chromosome 6) glucuronidates sexual steroids and bile acids. Oxazepam and lorazepam are mainly metabolized by glucuronidation. Anti-epileptics with mood-stabilizing properties are frequently metabolized by UGTs. Opioid and nicotine addiction may also be influenced by glucuronidation. Glucuronidation of serotonin may be important during fetal development. UGTs appear to be in small concentrations in brain tissue (and higher concentrations at brain capillaries). However, UGTs may be localized in certain brain areas to provide a neuroprotective function. This review illustrates the importance of glucuronidation and the implications for psychiatry.

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Hepatic enzyme induction patterns and phenothiazine side effects

Cited by 5 publications

References 1 publication

Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls

Metabolomic Profiling of Post-Mortem Brain Reveals Changes in Amino Acid and Glucose Metabolism in Mental Illness Compared with Controls

Enzyme Induction by Moricizine: Time Course and Extent in Healthy Subjects

Glucuronidation enzymes, genes and psychiatry

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