Search

The purpose of this study was to investigate the potential clinical relevance of estimating the apparent clearance (CL/F) of atorvastatin through population pharmacokinetic (PopPK) modeling with samples collected in a real-life setting in a cohort of ambulatory patients at risk of cardiovascular disease by using an opportunistic sampling strategy easily accessible in clinical routine. A total of 132 pharmacokinetic (PK) samples at a maximum of three visits were collected in the 70 included patients. The effects of demographic, genetic, and clinical covariates were also considered. With the collected data, we developed a two-compartment PopPK model that allowed estimating atorvastatin CL/F relatively precisely and considering the genotype of the patient for SLCO1B1 c.521T>C single-nucleotide polymorphism (SNP). Our results indicate that the estimation of the CL/F of atorvastatin through our PopPK model might help in identifying patients at risk of myalgia. Indeed, we showed that a patient presenting a CL/F lower than 414.67 L h-1 is at risk of suffering from muscle discomfort. We also observed that the CL/F was correlated with the efficacy outcomes, suggesting that a higher CL/F is associated with a better drug efficacy (i.e., a greater decrease in total and LDL-cholesterol levels). In conclusion, our study demonstrates that PopPK modeling can be useful in daily clinics to estimate a patient' atorvastatin clearance. Notifying the clinician with this information can help in identifying patients at risk of myalgia and gives indication about the potential responsiveness to atorvastatin therapy.

Aim: ABCB1 (or P-glycoprotein) is implicated in the multidrug-resistance phenotype, including the resistance toward anticancer drugs such as tyrosine kinase inhibitors (TKIs). The purpose of this study was to evaluate in vitro the influence of the ABCB1 1199G>A SNP on ABCB1 transport activity toward selected TKIs (imatinib, nilotinib and dasatinib) that are currently used in chronic myelogenous leukemia. Material & methods: Two different cell lines, HEK293 and K562, were stably transfected with ABCB1 1199G wild-type or ABCB1 1199A variant allele. The impact of this polymorphism on accumulation and antiproliferative effects of imatinib, nilotinib and dasatinib was evaluated. Results: In K562 models, the expression of Asn400 variant protein was associated with lower antiproliferative effects of imatinib, nilotinib and dasatinib compared with Ser400 wild-type protein. Moreover, in HEK293 cells, imatinib and nilotinib intracellular accumulation were lower in variant compared with wild-type models. Conclusion: Imatinib, nilotinib and dasatinib are transported more efficiently by the ABCB1 variant (Asn400) compared with the wild-type (Ser400) protein. The impact of ABCB1 1199G>A SNP on TKI response should be further investigated in chronic myelogenous leukemia patients.

BACKGROUND: We tested the hypothesis that vardenafil, a common drug used for improving erectile dysfunction and able to partially normalize transepithelial chloride transport in cystic fibrosis (CF), modulates CF lung inflammation. METHODS: Inflammatory markers in lungs of F508del-CF and wild-type mice were monitored in response to lipopolysaccharide from Pseudomonas aeruginosa (LPS). The effect of pretreatment with vardenafil (0.14 mg/kg) was evaluated. RESULTS: A latent inflammatory status, characterized by neutrophil infiltrate, mouse macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-α, was found in baseline conditions in F508del-CF mice. Inflammatory markers were increased after LPS with higher responses in CF. Vardenafil globally attenuated inflammatory responses in both genotypes however reduction of macrophage infiltration, macrophage chemoattractant chemokine and interleukin-1β was observed in the CF group only. CONCLUSION: Vardenafil reduces lung inflammation with a more pronounced effect in F508del-CF mice, particularly on macrophage cell markers.

Overexpression of ABCB1 (also called P-glycoprotein) confers resistance to multiple anticancer drugs, including tyrosine kinase inhibitors (TKIs). Several ABCB1 single nucleotide polymorphisms affect the transporter activity. The most common ABCB1 variants are 1236C > T, 2677G > T, 3435C > T and have been associated with clinical response to imatinib in chronic myelogenous leukaemia (CML) in some studies. We evaluated the impact of these polymorphisms on the anti-proliferative effect and the intracellular accumulation of TKIs (imatinib, nilotinib, dasatinib and ponatinib) in transfected HEK293 and K562 cells. ABCB1 overexpression increased the resistance of cells to doxorubicin, vinblastine and TKIs. Imatinib anti-proliferative effect and accumulation were decreased to a larger extent in cells expressing the ABCB1 wild-type protein compared with the 1236T-2677T-3435T variant relatively to control cells. By contrast, ABCB1 polymorphisms influenced the activity of nilotinib, dasatinib and ponatinib to a much lesser extent. In conclusion, our data suggest that wild-type ABCB1 exports imatinib more efficiently than the 1236T-2677T-3435T variant protein, providing a molecular basis for the reported association between ABCB1 polymorphisms and the response to imatinib in CML. Our results also point to a weaker impact of ABCB1 polymorphisms on the activity of nilotinib, dasatinib and ponatinib.

Objectives: Having recently demonstrated that vardenafil, a phosphodiesterase type 5 inhibitor, reduces LPS-induced inflammatory responses in CF mice, we hypothesized that CF macrophages are characterized by a pro-inflammatory phenotype which can be modulated by vardenafil. We also want to study the role of CFTR in this vardenafil-induced immunomodulation of macrophages. Methods: Macrophages were purified from lung homogenates from homozygous F508del-CFTR, CFTR-/- (KO) and wild-type (WT) mice. To test the hypothesis that macrophages activity is altered in F508del-CF and KO mice, macrophages differentiation in pro-inflammatory (M1) effectors was studied after polarization with LPS and IFN-γ. Pro-inflammatory mediators TNF-α and NOS-2 were quantified by ELISA or by quantitative RT-PCR. Results: F508del-CF lung macrophages displayed an exaggerated pro-inflammatory response to M1 mediators. Both TNF-α and NOS-2 levels were more than doubled. Similar observations were made in macrophages isolated from KO mice, confirming that loss of CFTR promotes pro-inflammatory phenotype in macrophages. In F508del-CF mice, vardenafil reduced the expression of pro-inflammatory mediators by at least 50%. However, vardenafil failed to normalize TNF-α and NOS-2 expression in KO macrophages, suggesting that the presence of CFTR protein is required for immunomodulation by vardenafil. Conclusion: Taken together, our results indicate that macrophages display a pro-inflammatory profile and play a critical role in inflammatory responses in CF. Moreover, the immunomodulatory effect of vardenafil, which could thus be beneficial in CF pharmacotherapy, requires CFTR expression.