title: Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques.
abstract: The liver is crucial to pharmacology, yet substantial knowledge gaps exist in the understanding of its basic pharmacologic processes. An improved understanding for humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats by using samples collected by fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical resection. Thirteen Sprague-Dawley rats were evaluated, nine of which received paritaprevir/ritonavir at 30/20 mg/kg of body weight by oral gavage daily for 4 or 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3, or 5 passes (FNA1, FNA3, and FNA5); via CNB (16G needle); and via surgical resection. Drug concentrations in plasma were also assessed. Analyses included noncompartmental pharmacokinetic analysis and use of Bland-Altman techniques. All liver tissue samples had higher paritaprevir and ritonavir concentrations than those in plasma. Resected samples, considered the benchmark measure, resulted in estimations of the highest values for the pharmacokinetic parameters of exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between tissue resection and CNB, with 15% bias, followed by FNA3and FNA5, with 18% bias, and FNA1and FNA3, with a 22% bias for paritaprevir. Paritaprevir and ritonavir are highly concentrated in rat liver. Further research is needed to validate FNA sampling for humans, with the possible derivation and application of correction factors for drug concentration measurements.
authors.affiliation: Department of Neurology, Center for Human Experimental Therapeutics, University of Rochester, Rochester, New York, USA.|AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Venuto
authors.affiliation: Department of Biostatistics, University at Buffalo, Buffalo, New York, USA.
authors.forename: Marianthi
authors.initials: M
authors.lastname: Markatou
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University at Buffalo, Buffalo, New York, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Woolwine-Cunningham
authors.affiliation: Department of Flow & Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Furlage
authors.affiliation: AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ocque
authors.affiliation: AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: DiFrancesco
authors.affiliation: AbbVie Inc., North Chicago, Illinois, USA.
authors.forename: Emily O
authors.initials: EO
authors.lastname: Dumas
authors.affiliation: Department of Flow & Image Cytometry, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Wallace
authors.affiliation: AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.affiliation: Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University at Buffalo, Buffalo, New York, USA ahtalal@buffalo.edu.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Talal
mesh_terms: D000818:Animals; D044963:Biopsy, Fine-Needle; D002853:Chromatography, Liquid; D003521:Cyclopropanes; D022781:Hepatocytes / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000502:physiology; D047029:Lactams, Macrocyclic; D008099:Liver / Q000378:metabolism* / Q000601:surgery; D047028:Macrocyclic Compounds / Q000493:pharmacokinetics*; D008297:Male; D011392:Proline / Q000031:analogs & derivatives; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000493:pharmacokinetics*; D013449:Sulfonamides; D053719:Tandem Mass Spectrometry
chemical_list: D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; D011392:Proline; D019438:Ritonavir; C585405:paritaprevir
keywords: hepatocyte isolation; liver biopsy; liver drug concentration; liver fine-needle aspiration