Phenotyping Indices of CYP450 and P-Glycoprotein in Human Volunteers and in Patients Treated with Painkillers or Psychotropic Drugs
Léa Darnaud,
Clément Delage,
Youssef Daali,
Anne-Priscille Trouvin,
Serge Perrot,
Nihel Khoudour,
Nadia Merise,
Laurence Labat,
Bruno Etain,
Frank Bellivier,
Célia Lloret-Linares,
Vanessa Bloch,
Emmanuel Curis,
Xavier Declèves
Affiliations
Léa Darnaud
Biologie du Médicament—Toxicologie, AP-HP, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75679 Paris, France
Clément Delage
Faculty of Health, Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France
Youssef Daali
Division of Clinical Pharmacology and Toxicology, Department of Anesthesiology, Pharmacology, Intensive Care and Emergency Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland
Anne-Priscille Trouvin
Centre de la Douleur, AP-HP, Hôpital Cochin, 75679 Paris, France
Serge Perrot
Centre de la Douleur, AP-HP, Hôpital Cochin, 75679 Paris, France
Nihel Khoudour
Biologie du Médicament—Toxicologie, AP-HP, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75679 Paris, France
Nadia Merise
Biologie du Médicament—Toxicologie, AP-HP, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75679 Paris, France
Laurence Labat
Faculty of Health, Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France
Bruno Etain
Faculty of Health, Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France
Frank Bellivier
Faculty of Health, Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France
Célia Lloret-Linares
Ramsay Santé—Hôpital Privé Pays de Savoie, 74100 Annemasse, France
Vanessa Bloch
Faculty of Health, Université Paris Cité, Inserm, UMRS-1144, Optimisation Thérapeutique en Neuropsychopharmacologie, 75006 Paris, France
Emmanuel Curis
Faculté de Pharmacie de Paris, Université Paris Cité, UR 7537 BioSTM, 75006 Paris, France
Xavier Declèves
Biologie du Médicament—Toxicologie, AP-HP, Hôpital Cochin, 27 rue du Faubourg St. Jacques, 75679 Paris, France
Drug-metabolizing enzymes and drug transporters are key determinants of drug pharmacokinetics and response. The cocktail-based cytochrome P450 (CYP) and drug transporter phenotyping approach consists in the administration of multiple CYP or transporter-specific probe drugs to determine their activities simultaneously. Several drug cocktails have been developed over the past two decades in order to assess CYP450 activity in human subjects. However, phenotyping indices were mostly established for healthy volunteers. In this study, we first performed a literature review of 27 clinical pharmacokinetic studies using drug phenotypic cocktails in order to determine 95%,95% tolerance intervals of phenotyping indices in healthy volunteers. Then, we applied these phenotypic indices to 46 phenotypic assessments processed in patients having therapeutic issues when treated with painkillers or psychotropic drugs. Patients were given the complete phenotypic cocktail in order to explore the phenotypic activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A, and P-glycoprotein (P-gp). P-gp activity was evaluated by determining AUC0–6h for plasma concentrations over time of fexofenadine, a well-known substrate of P-gp. CYP metabolic activities were assessed by measuring the CYP-specific metabolite/parent drug probe plasma concentrations, yielding single-point metabolic ratios at 2 h, 3 h, and 6 h or AUC0–6h ratio after oral administration of the cocktail. The amplitude of phenotyping indices observed in our patients was much wider than those observed in the literature for healthy volunteers. Our study helps define the range of phenotyping indices with “normal” activities in human volunteers and allows classification of patients for further clinical studies regarding CYP and P-gp activities.
