1.
In vitro and in vivo human metabolism and pharmacokinetics of S- and R-praziquantel.
Kapungu, NN, Li, X, Nhachi, C, Masimirembwa, C, Thelingwani, RS
Pharmacology research & perspectives. 2020;(4):e00618
Abstract
Racemic praziquantel (PZQ) is the drug of choice for the treatment of schistosomiasis. R-Praziquantel (R-PZQ) has been shown as the therapeutic form, whereas S-PZQ is less efficacious and responsible for the bitter taste of the tablet. This study aimed at investigating the metabolism of R- and S-PZQ as this could have implications on efficacy and safety of racemate and R-PZQ specific formulations under development. In vitro CYP reaction phenotyping assay using 10 recombinant CYP (rCYP) isoenzymes showed hepatic CYP1A2, 2C19, 2D6, 3A4, and 3A5 were the major enzymes involved in metabolism of PZQ. Enzyme kinetic studies were performed by substrate depletion and metabolite formation methods, by incubating PZQ and its R- or S-enantiomers in human liver microsomes (HLM) and the rCYP enzymes. The effect of selective CYP inhibitors on PZQ metabolism was assessed in HLM. CYP1A2, 2C19, and 3A4 exhibited different catalytic activity toward PZQ, R- and S-enantiomers. Metabolism of R-PZQ was mainly catalyzed by CYP1A2 and CYP2C19, whereas metabolism of S-PZQ was mainly by CYP2C19 and CYP3A4. Based on metabolic CLint obtained through formation of hydroxylated metabolites, CYP3A4 was estimated to contribute 89.88% to metabolism of S-PZQ using SIMCYP® IVIVE prediction. Reanalysis of samples from a human PZQ-ketoconazole (KTZ) drug-drug interaction pharmacokinetic study confirmed these findings in that KTZ, a potent inhibitor of CYP3A, selectively increased area under the curve of S-PZQ by 68% and that of R-PZQ by just 9%. Knowledge of enantioselective metabolism will enable better understanding of variable efficacy of PZQ in patients and the R-PZQ formulation under development.
2.
Influences of Smoking Status on Effectiveness of Cytochrome P450 Enzyme System Metabolized Medications in Reducing In-Hospital Death in 14 658 Patients With Acute Myocardial Infarction: Data From CPACS-3 Study.
Li, M, Feng, L, Li, X, Gao, R, Wu, Y
Journal of cardiovascular pharmacology and therapeutics. 2020;(5):418-424
Abstract
BACKGROUND The benefit of cytochrome P450 (CYP450) enzyme system metabolized medications, especially clopidogrel, was reported more pronounced in smoking than nonsmoking patients, but limited evidence was available from Asian patients. We analyzed data from a large registry-based study of Chinese patients with acute myocardial infarction (AMI) to understand if the above finding could be reproduced. METHODS A total of 14 658 patients with AMI were prospectively recruited from 101 hospitals across China. Generalized estimating equation was applied to assess the association between CYP450 enzyme system metabolized medications (clopidogrel, statins, calcium channel blockers) and in-hospital death in smoking and nonsmoking patients, separately, adjusting for hospital clustering effects and propensity score of using the medication in question. RESULTS There were 86%, 93%, and 10% of study patients who received clopidogrel, statins, and calcium channel blockers during the hospitalization. Compared with patients not receiving clopidogrel, patients receiving the drug had a significantly lower risk of in-hospital death (adjusted relative risk [RR] = 0.61, 95% confidence interval [CI]: 0.40-0.91) in current smokers but an insignificant lower risk (adjusted RR = 0.85, 95% CI: 0.71-1.01) in nonsmokers, and the P for interaction was <.01. The corresponding adjusted RR was 0.45 (95% CI: 0.24-0.86) in current smokers and 0.94 (95% CI: 0.68-1.29) in nonsmokers (P for interaction <.01) for statins use and 1.00 (95% CI: 0.53-1.89) in current smokers and 0.66 (95% CI: 0.48-0.90) in nonsmokers (P for interaction = .23) for calcium channel blockers use. CONCLUSIONS Our study in a large cohort of Chinese patients with AMI found that the treatment effect in reducing risk of in-hospital death was significantly larger in smokers than in nonsmokers as for clopidogrel and statins but not for calcium channel blockers.