title: Evaluation of 6β-Hydroxycortisol and 6β-Hydroxycortisone as Biomarkers for Cytochrome P450 3A Activity: Insight into Their Predictive Value for Estimating Oral Immunosuppressant Metabolism.
abstract: The combined clearance of endogenous 6β-hydroxycortisol and 6β-hydroxycortisone is suggested biomarker for in vivo cytochrome P450 3A (CYP3A) activity. We aimed to determine whether the combined clearance of these two markers together with information of biopharmaceutics classification system (BCS) of drugs could be used to predict CYP3A-mediated metabolism of immunosuppressants. The BCS of drug formulations were determined based on the solubility and permeability. Sixty-seven healthy subjects were divided into three groups and group 1 (n = 23), 2 (n = 22), and 3 (n = 22) received oral single dose of cyclosporine, tacrolimus, and sirolimus, respectively. Blood and urine samples were gathered at various times. The combined clearance of 6β-hydroxycortisol and 6β-hydroxycortisone correlated significantly with cyclosporine pharmacokinetics (p < 0.001) after oral dose of a BCS 1 formulation, whereas no relationships were seen after administration of tacrolimus and sirolimus formulations, both of which belonged to BCS 2. Regarding the biopharmaceutical characteristics, the endogenous CYP3A biomarker explains 74.5% of variability in oral cyclosporine clearance between individuals.
authors.affiliation: School of Life Sciences, Central South University, Changsha, Hunan, China.|School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.|The State Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Pharmacy, Zhangzhou Municipal Hospital of Fujian Province, Zhangzhou, Fujian, China.
authors.forename: Ningfang
authors.initials: N
authors.lastname: Cai
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Yang
authors.affiliation: Haikou People's Hospital and Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou, Hainan, China.
authors.forename: Xiaoai
authors.initials: X
authors.lastname: He
authors.affiliation: School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Cheng
mesh_terms: D015415:Biomarkers / Q000032:analysis; D001702:Biopharmaceutics; D002626:Chemistry, Pharmaceutical; D003348:Cortisone / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000032:analysis / Q000493:pharmacokinetics; D007166:Immunosuppressive Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D011237:Predictive Value of Tests; D020123:Sirolimus / Q000493:pharmacokinetics; D016559:Tacrolimus / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C485511:6 beta-hydroxycortisone; D015415:Biomarkers; D007166:Immunosuppressive Agents; C001380:6 beta-hydroxycortisol; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D003348:Cortisone; D020123:Sirolimus; D006854:Hydrocortisone; D016559:Tacrolimus
keywords: biopharmaceutics classification system; cytochrome P450; drug metabolizing enzymes; pharmacokinetics; phenotype