title: Pharmacokinetic modeling of enterohepatic circulation of mycophenolic acid in renal transplant recipients.
abstract: Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure.
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Barcelona, Barcelona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Colom
authors.affiliation: 1] Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain [2] Pharmacogenetic group of the Symphony Study in Spain, Barcelona, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Lloberas
authors.affiliation: 1] Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Barcelona, Barcelona, Spain [2] Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Franc
authors.initials: F
authors.lastname: Andreu
authors.affiliation: Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Caldés
authors.affiliation: Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.affiliation: Nephrology Service, Hospital Clinic i Provincial, Barcelona, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Oppenheimer
authors.affiliation: Nephrology Service, Hospital La Fe, Valencia, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Sanchez-Plumed
authors.affiliation: Nephrology Service, Hospital Virgen del Rocío, Sevilla, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gentil
authors.affiliation: Department of Nephrology and Transplantation University Hospital, Leuven, Belgium.
authors.forename: Dirk R
authors.initials: DR
authors.lastname: Kuypers
authors.affiliation: Centre de Diagnostic Biomedic, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Brunet
authors.affiliation: Department of Nephrology and Transplantation University Hospital, Malmö, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.affiliation: Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004764:Enterohepatic Circulation; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D020123:Sirolimus / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage; D055815:Young Adult
chemical_list: D016572:Cyclosporine; D007166:Immunosuppressive Agents; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus