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Role of Metabolism in Chemically Induced Nephrotoxicity
Published in Robin S. Goldstein, Mechanisms of Injury in Renal Disease and Toxicity, 2020
Although the sulfoxidation reaction is present in both hepatic and renal microsomes, the rate of sulfoxide formation by kidney is nearly threefold greater than that by liver (Sausen and Elfarra, 1990a; Sausen et al., 1993). This greater activity combined with the specificity of membrane transport systems may account for the organ specificity pattern.
Clinical Pharmacology of the Anti-Tuberculosis Drugs
Published in Lloyd N. Friedman, Martin Dedicoat, Peter D. O. Davies, Clinical Tuberculosis, 2020
Gerry Davies, Charles Peloquin
Oral bioavailability is believed to be near 100%182 and is not significantly affected by food (4% change in AUC).183 The volume of distribution is 3.2 L/kg and protein binding is 10%–30%. Both drugs have a complex metabolic pathway involving sulfoxidation, desulfuration, and deamination followed by methylation, and the sulfoxide metabolites are active. Less than 1% of the drugs are excreted unchanged in the urine. The t1/2 of ETH is 1.9 hours and predicted Cmax is 0.9 μg/mL and AUC 14.4 μg/mL × hour at a dose of 500 mg twice daily.184 In a recent study of PTH t1/2 was 2.7 hours, Cmax is 2.2 μg/mL and AUC 11 μg/mL × hour at a dose or 250–375 mg twice daily.185 ETM is concentrated 9.7-fold in epithelial lining fluid though concentrations in alveolar cells are 50% or less of plasma.102 No information is available on penetration into lesions. CSF concentrations of ETH are approximately 80% of those in plasma.14 Penetration data are not available for PTM.
Drug-Induced Vanishing Bile Duct Syndromes
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Tania A. Roskams, Valeer J. Desmet
Numerous host factors appear to enhance susceptibility for drug-induced liver disease for a variety of agents,44 including those resulting in drug-induced vanishing bile duct syndrome. Genetic predispositions have been described for a small number of drugs and may comprise a defect in protective mechanisms (e.g., sulfoxidation deficiency in chlorpromazine toxicity45) and/or a particular haplotype.44,45 For amoxycillin/clavulanic acid (Augmentin) toxicity, a strong association with the DRB1*1501-DRB5*0101-DQB*0602 haplotype was found.46,47 Those patients carrying the haplotype are more prone to develop a cholestatic or mixed type liver damage than a hepatocellular pattern. Whether this observation suggests that the destruction of bile ducts is triggered by an immune mechanism or represents a link with other genes that are responsible for modifying the metabolism of the drug, remains to be elucidated.47 Other host factors include gender, age differences, quality of nutrition, pregnancy, extrahepatic diseases and degree of alcohol consumption.44,48
Predicting plasma concentration of quetiapine in patients with depression using machine learning techniques based on real-world evidence
Published in Expert Review of Clinical Pharmacology, 2023
Lin Yang, Jinyuan Zhang, Jing Yu, Ze Yu, Xin Hao, Fei Gao, Chunhua Zhou
Quetiapine is a dibenzothiazepine derivative, approved for adjuvant therapy for major depression. It undergoes substantial sulfoxidation in the liver to produce its main but inactive sulfoxide metabolite, as well as by N- and O-dealkylation, which are less efficient metabolic routes. CYP3A4 appears to be the main isoenzyme implicated in these metabolic events, while CYP2D6 May only have a modest impact [24]. Studies have shown that within a week of treatment, quetiapine can sometimes be distinguished from placebo, and it can improve the effect of antidepressants or make antidepressants work for patients that medications did not work in the present depression episode [25–27]. Quetiapine is an antipsychotic drug which is most frequently prescribed to adults between the ages of 20 and 64 with expanding use across the globe [28]. Both quetiapine and norquetiapine bind to the histaminergic (HRH1) and adrenergic alpha 1 (ADRA1) receptors with relevant affinity and antagonistic activity, which may result in symptoms including drowsiness and hypotension [29,30]. Additionally, norquetiapine binds to muscarinic (CHRM1) receptors as well, which could result in the frequently noticed anticholinergic side effects such as tachycardia, dry mouth, and constipation [16,24]. Quetiapine can lead to metabolic issues such as weight gain, hyperglycemia, and dyslipidemia as well [31].
Optimization and in vivo evaluation of quetiapine-loaded transdermal drug delivery system for the treatment of schizophrenia
Published in Drug Development and Industrial Pharmacy, 2020
Milan B. Agrawal, Mayur M. Patel
Quetiapine is an atypical antipsychotic agent categorized as a serotonin antagonist that binds to 5-HT 2 A/2C receptors. It has an immense affinity for various dopaminergic receptors though exerts weak antagonism for the D2 receptor which is accountable for modulating the neuroleptic effect [3]. Quetiapine tablets are taken twice daily, orally where it undergoes the extensive hepatic first-pass metabolism resulting in very less bioavailability of quetiapine which is reported to be less than 9% [4]. Quetiapine is majorly metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive [5]. Hence, the delivery of quetiapine is a difficult task for the successful treatment of schizophrenia, where lengthy therapy is mandatory for the patients who may need help for receiving medication by conventional routes.
Phenylalanine 4-monooxygenase: the “sulfoxidation polymorphism”
Published in Xenobiotica, 2020
Stephen C. Mitchell, Glyn B. Steventon
S-carboxymethyl-l-cysteine has been widely employed as a mucolytic agent (Joullié et al., 1961) and has been shown to possess free-radical scavenging and anti-inflammatory properties (Hooper & Calvert, 2008). The drug undergoes extensive metabolism via the pathways of sulfoxidation, N-acetylation, decarboxylation, deamination and glucuronide formation (Mitchell & Steventon, 2012). It is the particular pathway of sulfur oxygenation that appears paramount in determining therapeutic efficacy. The removal of damaging reactive oxygen species requires the sacrificial oxygenation of the sulfide moiety within the molecule, thereby forming a stable sulfoxide derivative (Brandolini et al., 2003). Hence, the parent sulfide is therapeutically active whereas the sulfoxide metabolite is not. Any additional process that produces the sulfoxide species will therefore deplete the amount of sulfide available. It follows that if individuals differ in their metabolic ability to undertake this sulfoxidation reaction then the amounts of active sulfide would vary, with poor sulfoxidisers having the advantage. Benefit could also be achieved by administering the dose at night-time (Mitchell & Steventon, 2012).