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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Clozapine is the first atypical antipsychotic developed and is first introduced in Europe in 1971 but is voluntarily withdrawn by the manufacturer in 1975 after it is shown to cause agranulocytosis that leads to death in some clozapine-treated patients. In 1989, the FDA approved clozapine’s use for treatment-resistant schizophrenia on the basis of the studies demonstrating that clozapine is more effective than any other antipsychotic for treating schizophrenia. The main metabolic pathways of clozapine consist of N-demethylation and N-oxide formation (Byerly and DeVane 1996). CYP1A2, 3A4, 2C9, 2C19, and 2D6 N-demethylate clozapine, while N-oxide formation is catalyzed by CYP3A4, 1A2, and flavin-containing monooxygenase 3 (FMO3) (Figure 3.22) (Eiermann et al. 1997; Fang et al. 1998; Linnet and Olesen 1997; Olesen and Linnet 2001; Tugnait et al. 1999). The estimated contribution of CYP1A2, 2C19, 3A4, 2C9, and 2D6 amounts to 30%, 24%, 22%, 12%, and 6%, respectively, with regard to the N-demethylation of clozapine in human liver microsomes (Olesen and Linnet 2001). CYP2D6 might play a role in the formation of metabolites other than N-demethylclozapine and the N-oxide (Fischer et al. 1992b). In addition, clozapine is extensively glucuronidated in vitro and in vivo by UGT1A4 (Mori et al. 2005).
Potential approaches using teneligliptin for the treatment of type 2 diabetes mellitus: current status and future prospects
Published in Expert Review of Clinical Pharmacology, 2023
Harmanjit Singh, Jasbir Singh, Ravneet Kaur Bhangu, Mandeep Singla, Jagjit Singh, Farideh Javid
Teneligliptin is a potent, selective, and long-lasting inhibitor of DPP-4 with a half-life of approximately 24 hours [11]. Within 2 hours after administration, the inhibition of plasma DPP-4 activity was found to be a maximum of 81.3% and 89.7% for 10 and 20 mg of teneligliptin, respectively. Even 24 hours after administration, the active concentration of GLP-1 in the plasma remains considerably lower with teneligliptin 10 mg and 20 mg [35]. Teneligliptin has a substantially greater affinity (around fivefold as compared to other agents like sitagliptin) for S1, S2, and S2 extensive subsites of DPP-4 enzyme; different reasons may contribute to this; teneligliptin contains a relatively rigid ‘J’ structure, formed by five rings, four of which are directly linked, and has little entropy loss when it binds to DPP-4. Also, the interaction of teneligliptin with sub-site S2 is due to the formation of hydrogen bond between its carbonyl group and Asn710ʹs side chain. Lately, there is strong hydrophobic interaction of teneligliptin (mediated by an anchor lock domain) with the S2 extensive sub-site of DPP-4 enzyme. In vivo, the binding of the anchor lock domain may be correlated with long residence times of DPP-4 inhibitors and long in vivo duration of action [36]. Teneligliptin has been found to be metabolized by cytochrome 3A4 and flavin-containing monooxygenase 3 (FMO3). About one-third of the excretion of teneligliptin is governed through the renal route, and almost two-thirds is found to be metabolized and eliminated by the liver and kidneys.
Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis
Published in Expert Opinion on Pharmacotherapy, 2022
In doses of 10–680 mg, fedratinib is rapidly absorbed without food; though low- and high-fat meals increased AUC and Cmax by 24% and 14%, respectively [42,43]. Time to maximum concentration is 2–4 hours following administration. Fedratinib is ≥90% plasma protein bound with steady state concentrations achieved after 15 days and apparent volume of 1770 L [42,43]. Fedratinib is metabolized by CYP3A4, CYP2C19, and flavin-containing monooxygenase-3; though 80% of circulating drug is unmodified fedratinib [42–45]. Elimination of radiolabeled fedratinib is 77% through fecal excretion with only 5% expelled in urine [42,43,46]. The effective half-life of fedratinib is 41 h with apparent clearance of 13 L/h in MF patients [29]. There was no observed impact of sex, age, body weight, or mild-moderate hepatic impairment on the pharmacokinetics of fedratinib [42,43,45,46]. Fedratinib levels increased 1.5- and 1.9-fold in the setting of moderate (creatinine clearance [CrCl], 30–59 cc/min) and severe (CrCl 15–29 cc/min) renal dysfunction, respectively, and dose reduction for to 200 mg is recommended in patients with CrCl 15–29 cc/min [42–46].
Differential effects of C-reactive protein levels on voriconazole metabolism at three age groups in allogeneic hematopoietic cell transplant recipients
Published in Journal of Chemotherapy, 2021
Xingxian Luo, Taifeng Li, Lei Hu, Silu Liu, Haiyan Zhao, Jiaqi Zhang, Yufei Feng, Lin Huang
In the present study, the median concentration of VRCZ was highest in adults (1.48 mg/L), followed by children aged 10–18 (0.85 mg/L), and the lowest was children aged 2–10 years (0.65 mg/L), which were partly consistent with wei et al reported.10 Conversely, the order of the magnitude of the MR values was aged in 2–10 years (1.72), then in 11–18 years (1.21) and followed in 19–60 years (0.95), further verifying that metabolic rate of VRCZ exhibits negative relationship with age groups. Mann–Whitney U test suggested that MR values in 11–18 and 19–60 years were significantly lower in age 2–10 years (p < .05), indicating a higher activity of CYP2C19 enzyme in age 2–10 years. Existing evidence support that higher metabolic activity of flavin-containing monooxygenase 3 (FMO3) and CYP2C19 are found in children compared with adults.23 A higher metabolic intensity of VRCZ in younger children would reduce the impact of inflammation on liver microsomal enzyme activity. With the increase of age, the impact of inflammation on VRCZ metabolism seemed to be more and more prominent.