Intracellular accumulation of boceprevir according to plasma concentrations and pharmacogenetics

Cusato, Jessica; Allegra, Sarah; Nicolò, Amedeo De; Boglione, Lucio; Fatiguso, Giovanna; Abdi, Adnan Mohamed; Castaldo, Giuseppe; Perri, Giovanni Di; D’Avolio, Antonio

doi:10.1016/j.ijantimicag.2015.01.019

Cited by 10 publications

(3 citation statements)

References 13 publications

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“…Therefore, the concentration of this drug in cerebrospinal fluid is 8-and 5-fold lower than the plasma concentration in dogs (Ziemniak et al, 1984) and humans (Somogyi and Gugler, 1983), respectively. Single-nucleotide polymorphisms in ABCB1 and SLC28A2 genes correlated with the intracellular accumulation of the anti-hepatitis C virus drug boceprevir in peripheral blood mononuclear cells (Cusato et al, 2015). Underprediction of cytochrome P450 (P450)-mediated drug drug interactions (DDIs) is observed when perpetrators are also substrates for uptake transporters .…”

Section: Introductionmentioning

confidence: 99%

Intracellular Unbound Atorvastatin Concentrations in the Presence of Metabolism and Transport

Kulkarni¹,

Korzekwa²,

Nagar³

2016

Journal of Pharmacology and Experimental Therapeutics

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Accurate prediction of drug target activity and rational dosing regimen design require knowledge of drug concentrations at the target. It is important to understand the impact of processes such as membrane permeability, partitioning, and active transport on intracellular drug concentrations. The present study aimed to predict intracellular unbound atorvastatin concentrations and characterize the effect of enzyme-transporter interplay on these concentrations. Single-pass liver perfusion studies were conducted in rats using atorvastatin (ATV, 1 mM) alone at 4°C and at 37°C in presence of rifampin (RIF, 20 mM) and 1-aminobenzotriazole (ABT, 1 mM), separately and in combination. The unbound intracellular ATV concentration was predicted with a five-compartment explicit membrane model using the parameterized diffusional influx clearance, active basolateral uptake clearance, and metabolic clearance.Chemical inhibition of uptake and metabolism at 37°C proved to be better controls relative to studies at 4°C. The predicted unbound intracellular concentration at the end of the 50-minute perfusion in the 1ABT , 1ABT1RIF, and the ATV-only groups was 6.5 mM, 0.58 mM, and 5.14 mM, respectively. The predicted total liver concentrations and amount recovered in bile were within 0.94-1.3 fold of the observed value in all groups. The fold difference in total liver concentration did not always extrapolate to the fold difference in predicted unbound concentration across groups. Together, these results support the use of compartmental modeling to predict intracellular concentrations in dynamic organ-based systems. These predictions can provide insight into the role of uptake transporters and metabolizing enzymes in determining drug tissue concentrations.

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Section: Introductionmentioning

confidence: 99%

Intracellular Unbound Atorvastatin Concentrations in the Presence of Metabolism and Transport

Kulkarni¹,

Korzekwa²,

Nagar³

2016

Journal of Pharmacology and Experimental Therapeutics

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“…Also concerning BOC, a study by our group suggested a positive and significant correlation between plasma and PBMC levels. Moreover, we revealed that plasma levels of S-BOC active isomer and a polymorphism in the vitamin D receptor were able to predict S-intracellular exposure, whereas SNPs in aldo-keto reductase 1, breast cancer resistance protein1and solute carrier family 28genes predicted S-TLV in PBMC/plasma ratio (30).…”

Section: Discussionmentioning

confidence: 95%

Intracellular and Plasma Trough Concentration and Pharmacogenetics of Telaprevir

et al. 2015

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PURPOSE: Triple therapy for HCV-1 infection consists in boceprevir or telaprevir, ribavirin and PEG-interferon. Telaprevir is a P-glycoprotein substrate and it is metabolized by CYP3A4/5. No data have been published on intracellular penetration of telaprevir. We determined peripheral blood mononuclear cells (PBMCs) and trough plasma S and R telaprevir isomers concentrations; moreover, we evaluated the influence of some single nucleotide polymorphisms (SNPs) on these pharmacokinetic data after 1 month of triple therapy in humans. METHODS: Plasma and intracellular telaprevir concentrations were determined at the end of dosing interval (Ctrough) using ULPC-MS/MS validated methods; allelic discrimination was performed through real-time PCR. RESULTS: Median telaprevir Ctrough plasma concentrations were 2579 ng/mL and 2233 ng/mL for the pharmacologically more active S, and R, enantiomers, respectively, with median S/R plasma ratio of 1.11. In PBMC, the medians were 6863 ng/mL and 1096 ng/mL for S and R, respectively, with median S/R being 5.73. The PBMC:plasma ratio for S was 2.59 for R. Plasma ribavirin concentrations were directly correlated with plasma S-telaprevir concentrations. In linear regression analysis, only CYP24A1_rs2585428 SNP (p=0.003) and body mass index (p=0.038) were able to predict S-telaprevir PBMC concentrations. CONCLUSIONS: Our preliminary data could increase the understanding of mechanisms underlying telaprevir intracellular and plasma exposure, suggesting the implementation of pharmacogenetics in these drug kinetic studies. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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“…In addition, we found associations among vitamin-D-pathway-related gene polymorphisms and SOF plasma exposure and the associated hepatocarcinoma [ 18 , 19 ]. Concerning previous anti-HCV therapies, we suggest that different SNPs play a role in influencing telaprevir and boceprevir intracellular (IC) exposures [ 20 , 21 ]. Bilal et al evaluated GS-331007 IC concentrations at day 10, highlighting higher concentrations in patients achieving SVR as compared to relapsers [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy

et al. 2022

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Sofosbuvir (SOF) is an HCV NS5B polymerase inhibitor, and GS-331007 is its major metabolite. The aim of this study was to investigate whether clinical and pharmacological factors could influence GS-331007 intracellular (IC) concentrations in peripheral blood mononuclear cells (PBMCs) associated with a sustained virological response in patients treated with SOF and ribavirin (RBV). Drug levels were analyzed using liquid chromatography at different days of therapy, whereas variants in genes encoding transporters and nuclear factors were investigated using real-time PCR. This study enrolled 245 patients treated with SOF; 245 samples were analyzed for pharmacogenetics and 50 were analyzed for IC pharmacokinetics. The GS-331007 IC concentration at 30 days was associated with its plasma concentration determinate at 30, 60 and 90 days of SOF-therapy and with daclatasvir concentrations at 7 days of therapy. No genetic polymorphism affected IC exposure. In linear multivariate analysis, ledipasvir treatment, baseline albumin and estimated glomerular filtration rate were significant predictors of IC exposure. This study presents data on an IC evaluation in a cohort of patients treated with SOF, also considering pharmacogenetics. These results could be useful for regions where SOF–RBV treatment is considered the standard of care; moreover, they could further deepen the knowledge of IC exposure for similar drugs in the future.

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Intracellular accumulation of boceprevir according to plasma concentrations and pharmacogenetics

Cited by 10 publications

References 13 publications

Intracellular Unbound Atorvastatin Concentrations in the Presence of Metabolism and Transport

Intracellular Unbound Atorvastatin Concentrations in the Presence of Metabolism and Transport

Intracellular and Plasma Trough Concentration and Pharmacogenetics of Telaprevir

Factors Influencing the Intracellular Concentrations of the Sofosbuvir Metabolite GS-331007 (in PBMCs) at 30 Days of Therapy

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