THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes

Alexander, Stephen P.H.; Fabbro, Doriano; Kelly, Eamonn; Mathie, Alistair; Peters, John A.; Veale, Emma L.; Armstrong, Jane F.; Faccenda, Elena; Harding, Simon D; Pawson, Adam J.; Southan, Christopher; Davies, Jamie A.; Boison, Detlev; Burns, Kathryn; Dessauer, Carmen W.; Gertsch, Jürg; Helsby, Nuala A.; Izzo, Angelo A.; Koesling, Doris; Ostrom, Rennolds S.; Pyne, Nigel J.; Pyne, Susan; Russwurm, Michael; Seifert, Roland; Stasch, Johannes Peter; Stelt, Mario van der; Vliet, Albert van der; Watts, Val J.; Wong, Szu Shen

doi:10.1111/bph.15542

Cited by 371 publications

(318 citation statements)

References 139 publications

(152 reference statements)

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 29 …”

Section: Methodsmentioning

confidence: 99%

Enhanced elimination of betamethasone in dichorionic twin pregnancies

Rodrigues

Benzi

Matos

et al. 2021

Brit J Clinical Pharma

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Aim: No study has evaluated the betamethasone pharmacokinetics in twin pregnancies according to chorionicity. This study aimed to describe and compare the betamethasone pharmacokinetic parameters in singleton and dichorionic (DC) and monochorionic twin pregnancies in the third trimester of pregnancy.Methods: Twenty-six pregnant women received 2 intramuscular doses of 6 mg of betamethasone sodium phosphate plus 6 mg betamethasone acetate due to preterm labour. Serial blood samples were collected for 24 hours after the first intramuscular dose of betamethasone esters. Betamethasone plasma concentrations were quantified using a validated liquid chromatography-tandem mass spectrometry analytical method, and the pharmacokinetic parameters were obtained employing a noncompartmental model. Preliminary data on the betamethasone placental transfer are also presented. Results:The geometric mean (95% confidence interval) of AUC were significantly different, respectively, in singleton pregnancies when compared to DC twins. Conclusion:Data from this study suggest that the presence of 2 foetoplacental units may increase the betamethasone metabolism by hepatic CYP3A4 and/or placental 11β-HSD2 enzymes. Pharmacokinetic-pharmacodynamic clinical studies are needed to investigate whether these betamethasone pharmacokinetic changes have clinical repercussions for the newborns and require dose adjustment in DC twin pregnancies.

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Section: Methodsmentioning

confidence: 99%

Enhanced elimination of betamethasone in dichorionic twin pregnancies

Rodrigues

Benzi

Matos

et al. 2021

Brit J Clinical Pharma

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org/ and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22 (Alexander et al, 2021).…”

Section: Methodsmentioning

confidence: 99%

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

Rivas

Yee

Addison

et al. 2022

British J Pharmacology

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Background and Purpose Despite the availability of a variety of treatment options, many asthma patients have poorly controlled disease with frequent exacerbations. Proteinase‐activated receptor‐2 (PAR2) has been identified in preclinical animal models as important to asthma initiation and progression following allergen exposure. Proteinase activation of PAR2 raises intracellular Ca2+, inducing MAPK and β‐arrestin signalling in the airway, leading to inflammatory and protective effects. We have developed C391, a potent PAR2 antagonist effective in blocking peptidomimetic‐ and trypsin‐induced PAR2 signalling in vitro as well as reducing inflammatory PAR2‐associated pain in vivo. We hypothesized that PAR2 antagonism by C391 would attenuate allergen‐induced acutely expressed asthma indicators in murine models. Experimental Approach We evaluated the ability of C391 to alter Alternaria alternata‐induced PAR2 signalling pathways in vitro using a human airway epithelial cell line that naturally expresses PAR2 (16HBE14o−) and a transfected embryonic cell line (HEK 293). We next evaluated the ability for C391 to reduce A. alternata‐induced acutely expressed asthma indicators in vivo in two murine strains. Key Results C391 blocked A. alternata‐induced, PAR2‐dependent Ca2+ and MAPK signalling in 16HBE14o− cells, as well as β‐arrestin recruitment in HEK 293 cells. C391 effectively attenuated A. alternata‐induced inflammation, mucus production, mucus cell hyperplasia and airway hyperresponsiveness in acute allergen‐challenged murine models. Conclusions and Implications To our best knowledge, this is the first demonstration of pharmacological intervention of PAR2 to reduce allergen‐induced asthma indicators in vivo. These data support further development of PAR2 antagonists as potential first‐in‐class allergic asthma drugs.

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“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY, 37 and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 38 …”

Section: Methodsmentioning

confidence: 99%

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

Duong

Nand

Patel

et al. 2022

Pharmacology Res & Perspec

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Treatment response to clopidogrel is associated with CYP2C19 activity through the formation of the active H4 metabolite. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model of clopidogrel and its metabolites for populations of European ancestry, to predict the pharmacokinetics in the Japanese population by CYP2C19 phenotype, and to investigate the effect of clinical and demographic factors. A PBPK model was developed and verified to describe the two metabolic pathways of clopidogrel (H4 metabolite, acyl glucuronide metabolite) for a population of European ancestry using plasma data from published studies. Subsequently, model predictions in the Japanese population were evaluated. The effects of CYP2C19 activity, fluvoxamine coadministration (CYP2C19 inhibitor), and population‐specific factors (age, sex, BMI, body weight, cancer, hepatic, and renal dysfunction) on the pharmacokinetics of clopidogrel and its metabolites were then characterized. The predicted/observed ratios for clopidogrel and metabolite exposure parameters were acceptable (twofold acceptance criteria). For all CYP2C19 phenotypes, steady‐state AUC0‐τ of the H4 metabolite was lower for the Japanese (e.g., EM, 7.69 [6.26–9.45] ng·h/ml; geometric mean [95% CI]) than European (EM, 24.8 [20.4–30.1] ng·h/ml, p < .001) population. In addition to CYP2C19‐poor metabolizer phenotype, fluvoxamine coadministration, hepatic, and renal dysfunction were found to reduce H4 metabolite but not acyl glucuronide metabolite concentrations. This is the first PBPK model describing the two major metabolic pathways of clopidogrel, which can be applied to populations of European and Japanese ancestry by CYP2C19 phenotype. The differences between the two populations appear to be determined primarily by the effect of varying CYP2C19 liver activity.

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THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes

Cited by 371 publications

References 139 publications

Enhanced elimination of betamethasone in dichorionic twin pregnancies

Enhanced elimination of betamethasone in dichorionic twin pregnancies

Proteinase‐activated receptor‐2 antagonist C391 inhibits Alternaria‐induced airway epithelial signalling and asthma indicators in acute exposure mouse models

A physiologically based pharmacokinetic model of clopidogrel in populations of European and Japanese ancestry: An evaluation of CYP2C19 activity

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