Comparative Hepatic and Intestinal Metabolism and Pharmacodynamics of Statins.

Biotransformation Cytochrome P-450 Enzyme System / metabolism Cytosol / metabolism Drug Design / methods Drug Development / methods Hepatobiliary Elimination Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry Inhibitory Concentration 50 Intestines / metabolism Liver / metabolism Metabolic Clearance Rate / drug effects Microsomes / physiology Network Pharmacology

Journal

Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Titre abrégé: Drug Metab Dispos
Pays: United States
ID NLM: 9421550

Informations de publication

Date de publication:
08 2021
Historique:
received: 04 02 2021
accepted: 05 05 2021
pubmed: 29 5 2021
medline: 24 3 2022
entrez: 28 5 2021
Statut: ppublish

Résumé

This study aimed to comprehensively investigate the in vitro metabolism of statins. The metabolism of clinically relevant concentrations of atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and their metabolites were investigated using human liver microsomes (HLMs), human intestine microsomes (HIMs), liver cytosol, and recombinant cytochrome P450 enzymes. We also determined the inhibitory effects of statin acids on their pharmacological target, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. In HLMs, statin lactones were metabolized to a much higher extent than their acid forms. Atorvastatin lactone and simvastatin (lactone) showed extensive metabolism [intrinsic clearance (CL

Identifiants

DOI: 10.1124/dmd.121.000406 PMID: 34045219
pubmed: 34045219
pii: dmd.121.000406
doi: 10.1124/dmd.121.000406
doi:

Substances chimiques

Hydroxymethylglutaryl-CoA Reductase Inhibitors 0
Cytochrome P-450 Enzyme System 9035-51-2

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

658-667

Informations de copyright

Copyright © 2021 by The Author(s).

Auteurs

Anne M Filppula (AM)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Päivi Hirvensalo (P)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Heli Parviainen (H)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Vilma E Ivaska (VE)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

K Ivar Lönnberg (KI)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Feng Deng (F)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Jenni Viinamäki (J)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Mika Kurkela (M)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Mikko Neuvonen (M)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.).

Mikko Niemi (M)

Department of Clinical Pharmacology and Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland (A.M.F., P.H., H.P., V.E.I., K.I.L., F.D., J.V., M.K., M.Ne., M.Ni.) and Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland (M.Ni.) mikko.niemi@helsinki.fi.

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Classifications MeSH

questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Pharmacocinétique › Biotransformation › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Cytosol › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Conception de médicament › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil buccodentaire et de l'appareil digestif › Phénomènes physiologiques de l'appareil digestif › Élimination hépatobiliaire › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Agents régulateurs du métabolisme des lipides › Hypolipémiants › Anticholestérolémiants › Inhibiteurs de l'hydroxyméthylglutaryl-CoA réductase › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Concentration inhibitrice 50 › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Système digestif › Tube digestif › Intestins › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Système digestif › Foie › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Pharmacocinétique › Taux de clairance métabolique › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Microsomes › Comparative Hepatic and Intestinal Metabolism...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Pharmacologie des réseaux › Comparative Hepatic and Intestinal Metabolism...