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Background and Aims: Gallstone disease (GSD) associates with significant morbidity and mortality. Decreased secretion of bile acids has been suggested as a driving factor for GSD. Recently, we linked the protein phosphatase 1 regulatory subunit 3 beta (PPP1R3B) rs4240624 genotype to decreased bile acid levels in bile. In this study, we investigated whether these individuals had an increased risk for GSD as well as the differences in the lipid composition of the gallbladder bile of these individuals compared to controls and patients with GSD. Methods: Bile acids, cholesterol, and phospholipid levels in gallbladder bile samples were enzymatically measured in 46 patients (34 female, age 45.7 ± 9.8 years, BMI 41.3 ± 4.4 kg/m2) who underwent elective laparoscopic Roux-en-Y gastric bypass. The lipidome of gallbladder bile was analyzed using high-performance liquid chromatography-mass spectrometry. Gallstone status was evaluated using abdominal ultrasonography before the surgery. Results: The G allele of PPP1R3B rs4240624 was significantly associated with GSD in patients with obesity. We validated this association in the UK Biobank. Bile lipidomics demonstrated that 13 of the 17 minor lipid classes measured were higher in individuals with the G allele. The concentrations of bile acids, cholesterol, and phospholipids, as well as the cholesterol saturation index, were lower in patients with GSD than in those without gallstones. GSD had an effect similar to that of PPP1R3B genotype on minor lipids. Conclusion: The PPP1R3B rs4240624 genotype is associated with gallstones and with changes in gallbladder bile similar to those observed in patients with gallstones, suggesting that the PPP1R3B genotype contributes to the risk of gallstones by altering the bile lipidome.
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Riboflavin (vitamin B2) has been proposed as a biomarker for breast cancer resistance protein (BCRP) activity. In recent studies in mice, cynomolgus monkeys, and humans, BCRP-inhibiting drugs increased the plasma concentration of riboflavin. We showed recently that ticagrelor inhibits BCRP and raises the plasma concentrations of the BCRP substrate rosuvastatin in healthy volunteers. In the same drug-drug interaction study, we now investigated whether ticagrelor affects the plasma concentrations of riboflavin. Intake of 90 mg ticagrelor increased the ratio between the peak plasma riboflavin concentration and the fasting riboflavin concentration before ticagrelor administration by 1.20-fold (90% confidence interval, 1.10-1.32; P = 0.006) compared to placebo. In vitro, riboflavin was transported by BCRP and multidrug-resistance-associated protein 4 (MRP4) but no clear transport was observed by MRP2, MRP3, or the P-glycoprotein. Moreover, ticagrelor inhibited the transport of riboflavin in BCRP- and MRP4-expressing membrane vesicles with unbound 50% inhibitory concentrations of 0.020 and 1.1 µM, respectively. Based on vesicle and tissue protein expression data, the small intestinal MRP4-mediated efflux clearance of riboflavin (1.2-1.4 nL/min/mg) was estimated to be similar to that mediated by BCRP (0.23-1.3 nL/min/mg). As MRP4 is expressed in the basolateral membrane of enterocytes, it may facilitate the absorption of riboflavin and impair the utility of riboflavin as a biomarker of intestinal BCRP. To conclude, ticagrelor modestly raises the plasma concentration of riboflavin probably by inhibiting intestinal BCRP. Inhibition of intestinal MRP4 may have reduced the absorption of riboflavin and limited the effect of ticagrelor on riboflavin levels.
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In a genome-wide association study of atorvastatin pharmacokinetics in 158 healthy volunteers, the SLCO1B1 c.521T>C (rs4149056) variant associated with increased area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of atorvastatin (P = 1.2 × 10-10), 2-hydroxy atorvastatin (P = 4.0 × 10-8), and 4-hydroxy atorvastatin (P = 2.9 × 10-8). An intronic LPP variant, rs1975991, associated with reduced atorvastatin lactone AUC0-∞ (P = 3.8 × 10-8). Three UGT1A variants linked with UGT1A3*2 associated with increased 2-hydroxy atorvastatin lactone AUC0-∞ (P = 3.9 × 10-8). Furthermore, a candidate gene analysis including 243 participants suggested that increased function SLCO1B1 variants and decreased activity CYP3A4 variants affect atorvastatin pharmacokinetics. Compared with individuals with normal function SLCO1B1 genotype, atorvastatin AUC0-∞ was 145% (90% confidence interval: 98-203%; P = 5.6 × 10-11) larger in individuals with poor function, 24% (9-41%; P = 0.0053) larger in those with decreased function, and 41% (16-59%; P = 0.016) smaller in those with highly increased function SLCO1B1 genotype. Individuals with intermediate metabolizer CYP3A4 genotype (CYP3A4*2 or CYP3A4*22 heterozygotes) had 33% (14-55%; P = 0.022) larger atorvastatin AUC0-∞ than those with normal metabolizer genotype. UGT1A3*2 heterozygotes had 16% (5-25%; P = 0.017) smaller and LPP rs1975991 homozygotes had 34% (22-44%; P = 4.8 × 10-5) smaller atorvastatin AUC0-∞ than noncarriers. These data demonstrate that genetic variation in SLCO1B1, UGT1A3, LPP, and CYP3A4 affects atorvastatin pharmacokinetics. This is the first study to suggest that LPP rs1975991 may reduce atorvastatin exposure. [Correction added on 6 April, after first online publication: An incomplete sentence ("= 0.017) smaller in heterozygotes for UGT1A3*2 and 34% (22%, 44%; P × 10-5) smaller in homozygotes for LPP noncarriers.") has been corrected in this version.].
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Área Sob a Curva , Atorvastatina , Citocromo P-450 CYP3A , Estudo de Associação Genômica Ampla , Glucuronosiltransferase , Transportador 1 de Ânion Orgânico Específico do Fígado , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Atorvastatina/farmacocinética , Atorvastatina/sangue , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Genótipo , Glucuronosiltransferase/genética , Voluntários Saudáveis , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Variantes Farmacogenômicos , Proteínas com Domínio LIM/genética , Proteínas do Citoesqueleto/genéticaRESUMO
Our aim was to evaluate biomarkers for organic anion transporting polypeptide 1B1 (OATP1B1) function using a hypothesis-free metabolomics approach. We analyzed fasting plasma samples from 356 healthy volunteers using non-targeted metabolite profiling by liquid chromatography high-resolution mass spectrometry. Based on SLCO1B1 genotypes, we stratified the volunteers to poor, decreased, normal, increased, and highly increased OATP1B1 function groups. Linear regression analysis, and random forest (RF) and gradient boosted decision tree (GBDT) regressors were used to investigate associations of plasma metabolite features with OATP1B1 function. Of the 9152 molecular features found, 39 associated with OATP1B1 function either in the linear regression analysis (p < 10-5) or the RF or GBDT regressors (Gini impurity decrease > 0.01). Linear regression analysis showed the strongest associations with two features identified as glycodeoxycholate 3-O-glucuronide (GDCA-3G; p = 1.2 × 10-20 for negative and p = 1.7 × 10-19 for positive electrospray ionization) and one identified as glycochenodeoxycholate 3-O-glucuronide (GCDCA-3G; p = 2.7 × 10-16). In both the RF and GBDT models, the GCDCA-3G feature showed the strongest association with OATP1B1 function, with Gini impurity decreases of 0.40 and 0.17. In RF, this was followed by one GDCA-3G feature, an unidentified feature with a molecular weight of 809.3521, and the second GDCA-3G feature. In GBDT, the second and third strongest associations were observed with the GDCA-3G features. Of the other associated features, we identified with confidence two representing lysophosphatidylethanolamine 22:5. In addition, one feature was putatively identified as pregnanolone sulfate and one as pregnenolone sulfate. These results confirm GCDCA-3G and GDCA-3G as robust OATP1B1 biomarkers in human plasma.
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Glucuronídeos , Transportadores de Ânions Orgânicos , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Genótipo , BiomarcadoresRESUMO
Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug-drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1-mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, crossover study, 9 healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration-time curve (AUC) and peak plasma concentration 2.6-fold (90% confidence intervals: 1.8-3.8 and 1.7-4.0, P = 0.001 and P = 0.003), and prolonged its half-life from 3.1 to 6.6 hours (P = 0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3%-19%, P = 0.032). The N-desmethylrosuvastatin:rosuvastatin AUC0-10h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3-O-glucuronide, glycochenodeoxycholate 3-O-glucuronide, glycodeoxycholate 3-O-sulfate, and glycochenodeoxycholate 3-O-sulfate, or the sodium-taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than twofold in humans, probably mainly by inhibiting intestinal BCRP. Because the risk for rosuvastatin-induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.
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Neoplasias da Mama , Glucuronídeos , Humanos , Feminino , Rosuvastatina Cálcica/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ticagrelor , Estudos Cross-Over , Ácido Glicoquenodesoxicólico , Proteínas de Neoplasias/metabolismo , Interações Medicamentosas , Sulfatos/metabolismoRESUMO
AIMS: Ibrutinib is used in the treatment of certain B-cell malignancies. Due to its CYP3A4-mediated metabolism and highly variable pharmacokinetics, it is prone to potentially harmful drug-drug interactions. METHODS: In a randomized, placebo-controlled, three-phase crossover study, we examined the effect of the CYP3A4-inhibiting antifungal posaconazole on ibrutinib pharmacokinetics. Eleven healthy participants ingested repeated doses of 300 mg of posaconazole either in the morning or in the evening, or placebo. A single dose of ibrutinib (30, 70 or 140 mg, respectively) was administered at 9 AM, 1 or 12 h after the preceding posaconazole/placebo dose. RESULTS: On average, morning posaconazole increased the dose-adjusted geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-∞ ) and peak plasma concentration (Cmax ) of ibrutinib 9.5-fold (90% confidence interval [CI] 6.3-14.3, P < 0.001) and 8.5-fold (90% CI 5.7-12.8, P < 0.001), respectively, while evening posaconazole increased those 10.3-fold (90% CI 6.7-16.0, P < 0.001) and 8.2-fold (90% CI 5.2-13.2, P < 0.001), respectively. Posaconazole had no significant effect on the half-life of ibrutinib, but substantially reduced the metabolite PCI-45227 to ibrutinib AUC0-∞ ratio. There were no significant differences in ibrutinib pharmacokinetics between morning and evening posaconazole phases. CONCLUSIONS: Posaconazole increases ibrutinib exposure substantially, by about 10-fold. This interaction cannot be avoided by dosing the drugs 12 h apart. In general, a 70-mg daily dose of ibrutinib should not be exceeded during posaconazole treatment to avoid potentially toxic systemic ibrutinib concentrations.
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Adenina/análogos & derivados , Citocromo P-450 CYP3A , Intervenção Coronária Percutânea , Piperidinas , Triazóis , Humanos , Estudos Cross-Over , Área Sob a CurvaRESUMO
Poly ADP-ribose polymerase (PARP) inhibitors have been approved for the treatment of various cancers. They share a similar mechanism of action but have differences in pharmacokinetic characteristics and potential for drug-drug interactions (DDI). This study evaluated the potential ATP-binding cassette transporter-mediated interactions between PARP inhibitors (niraparib, olaparib and rucaparib) and statins (atorvastatin and rosuvastatin). We studied the inhibitory activity of PARP inhibitors on breast cancer resistance protein (BCRP), multidrug resistance-associated protein 3 (MRP3) and P-glycoprotein (P-gp) using vesicular transport assays and determined the concentrations required for 50% inhibition (IC50 ). Then, we predicted the increase of statin exposure followed by the administration of PARP inhibitors using a mechanistic static model. Rucaparib was the strongest inhibitor of BCRP-mediated rosuvastatin transport (IC50 13.7 µM), followed by niraparib (42.6 µM) and olaparib (216 µM). PARP inhibitors did not affect MRP3. While niraparib appeared to inhibit P-gp, the inhibition showed large variability. The inhibition of intestinal BCRP by rucaparib, niraparib and olaparib was predicted to elevate rosuvastatin exposure by 52%, 37% and 24%, respectively. The interactions between PARP inhibitors and rosuvastatin are probably of minor clinical significance alone, but combined with other predisposing factors, they may increase the risk of rosuvastatin-associated adverse effects.
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OBJECTIVE: The association of SLCO1B1 c.521T>C with simvastatin-induced muscle toxicity is well characterized. However, different statins are subject to metabolism and transport also by other proteins exhibiting clinically meaningful genetic variation. Our aim was to investigate associations of SLCO1B1 c.521T>C with intolerance to atorvastatin, fluvastatin, pravastatin, rosuvastatin, or simvastatin, those of ABCG2 c.421C>A with intolerance to atorvastatin, fluvastatin, or rosuvastatin, and that of CYP2C9*2 and *3 alleles with intolerance to fluvastatin. METHODS: We studied the associations of these variants with statin intolerance in 2042 patients initiating statin therapy by combining genetic data from samples from the Helsinki Biobank to clinical chemistry and statin purchase data. RESULTS: We confirmed the association of SLCO1B1 c.521C/C genotype with simvastatin intolerance both by using phenotype of switching initial statin to another as a marker of statin intolerance [hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.08-3.25, P â =â 0.025] and statin switching along with creatine kinase measurement (HR 5.44, 95% CI 1.49-19.9, P â =â 0.011). No significant association was observed with atorvastatin and rosuvastatin. The sample sizes for fluvastatin and pravastatin were relatively small, but SLCO1B1 c.521T>C carriers had an increased risk of pravastatin intolerance defined by statin switching when compared to homozygous reference T/T genotype (HR 2.11, 95% CI 1.01-4.39, P â =â 0.047). CONCLUSION: The current results can inform pharmacogenetic statin prescribing guidelines and show feasibility for the methodology to be used in larger future studies.
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Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Atorvastatina/efeitos adversos , Rosuvastatina Cálcica/efeitos adversos , Pravastatina/efeitos adversos , Citocromo P-450 CYP2C9/genética , Fluvastatina/efeitos adversos , Farmacogenética , Sinvastatina/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Proteínas de Neoplasias/genéticaRESUMO
Drug interactions involving the inhibition of hepatic organic anion transporting polypeptides (OATPs) 1B1 and OATP1B3 are considered important. Therefore, we sought to study various sulfated bile acids (BA-S) as potential clinical OATP1B1/3 biomarkers. It was determined that BA-S [e.g., glycochenodeoxycholic acid 3-O-sulfate (GCDCA-S) and glycodeoxycholic acid 3-O-sulfate (GDCA-S)] are substrates of OATP1B1, OATP1B3, and sodium-dependent taurocholic acid cotransporting polypeptide (NTCP) transfected into human embryonic kidney 293 cells, with minimal uptake evident for other solute carriers (SLCs) like OATP2B1, organic anion transporter 2, and organic cation transporter 1. It was also shown that BA-S uptake by plated human hepatocytes (PHH) was inhibited (≥96%) by a pan-SLC inhibitor (rifamycin SV), and there was greater inhibition (≥77% versus ≤12%) with rifampicin (OATP1B1/3-selective inhibitor) than a hepatitis B virus myristoylated-preS1 peptide (NTCP-selective inhibitor). Estrone 3-sulfate was also used as an OATP1B1-selective inhibitor. In this instance, greater inhibition was observed with GDCA-S (76%) than GCDCA-S (52%). The study was expanded to encompass the measurement of GCDCA-S and GDCA-S in plasma of SLCO1B1 genotyped subjects. The geometric mean GDCA-S concentration was 2.6-fold (90% confidence interval 1.6, 4.3; P = 2.1 × 10-4) and 1.3-fold (1.1, 1.7; P = 0.001) higher in individuals homozygous and heterozygous for the SLCO1B1 c.521T > C loss-of-function allele, respectively. For GCDCA-S, no significant difference was noted [1.2-fold (0.8, 1.7; P = 0.384) and 0.9-fold (0.8, 1.1; P = 0.190), respectively]. This supported the in vitro data indicating that GDCA-S is a more OATP1B1-selective substrate (versus GCDCA-S). It is concluded that GCDCA-S and GDCA-S are viable plasma-based OATP1B1/3 biomarkers, but they are both less OATP1B1-selective when compared to their corresponding 3-O-glucuronides (GCDCA-3G and GDCA-3G). Additional studies are needed to determine their utility versus more established biomarkers, such as coproporphyrin I, for assessing inhibitors with different OATP1B1 (versus OATP1B3) inhibition signatures.
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Transportadores de Ânions Orgânicos , Humanos , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Sulfatos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Ácidos e Sais Biliares , Transporte Biológico/fisiologia , Biomarcadores/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismoRESUMO
Adverse effects are the major limiting factors in combinatorial chemotherapies. To identify genetic associations in ovarian cancer chemotherapy-induced toxicities and therapy outcomes, we examined a cohort of 101 patients receiving carboplatin-paclitaxel treatment with advanced high-grade serous ovarian cancers. Based on literature and database searches, we selected 19 candidate polymorphisms, designed a multiplex single nucleotide polymorphism-genotyping assay and applied Cox regression analysis, case-control association statistics and the log-rank Mantel-Cox test. In the Cox regression analysis, the SLCO1B3 rs1052536 AA-genotype was associated with a reduced risk of any severe toxicity (hazard ratio = 0.35, p = 0.023). In chi-square allelic test, the LIG3 rs1052536 T-allele was associated with an increased risk of neuropathy (odds ratio [OR] = 2.79, p = 0.031) and GSTP1 rs1695 G allele with a poorer response in the first-line chemotherapy (OR = 2.65, p = 0.026). In Kaplan-Meier survival analysis, ABCB1 rs2032582 TT-genotype was associated with shorter overall survival (uncorrected p = 0.025) and OPRM1 rs544093 GG and GT genotypes with shorter platinum-free interval (uncorrected p = 0.027) and progression-free survival (uncorrected p = 0.012). Results suggest that SLCO1B3 and LIG3 variants are associated with the risk of adverse effects in patients receiving carboplatin-paclitaxel treatment, the GSTP1 variant may affect the treatment response and ABCB1 and OPRM1 variants may influence the prognosis.
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Neoplasias Ovarianas , Humanos , Feminino , Carboplatina/efeitos adversos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Paclitaxel/efeitos adversos , Polimorfismo de Nucleotídeo Único , Genótipo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Glutationa S-Transferase pi/genética , Receptores Opioides mu/genética , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética , DNA Ligase Dependente de ATP/genética , Proteínas de Ligação a Poli-ADP-Ribose/genéticaRESUMO
Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of >10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2',7'-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T>C (p.106I>T), intracellular loop 2: c.629G>T (p.210G>V), c.633A>G (p.211I>M), c.639T>A (p.213N>L), transmembrane helix 6: 820A>G (p.274I>V), and the C-terminal end: 2005A>C (p.669N>H). Of these variants, SLCO1B1 c.629G>T (p.210G>V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G>T (p.210G>V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G>T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms.
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Transportador 1 de Ânion Orgânico Específico do Fígado , Transtornos Psicóticos , Humanos , Finlândia , Células HEK293 , Inibidores de Hidroximetilglutaril-CoA Redutases , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Rosuvastatina CálcicaRESUMO
We present 3 patients diagnosed with rhabdomyolysis 1-6 months after the initiation of concomitant rosuvastatin and ticagrelor medication. A literature review and Food and Drug Administration adverse event reporting system revealed >40 reports of rhabdomyolysis during concomitant ticagrelor and rosuvastatin, including 3 with a fatal outcome. We show that ticagrelor inhibits breast cancer resistance protein-, organic anion transporting polypeptide (OATP) 1B1-, 1B3- and 2B1-mediated transport of rosuvastatin in vitro with half-maximal unbound inhibitory concentrations of 0.36, 4.13, 7.5 and 3.26 µM, respectively. A static drug interaction model predicted that ticagrelor may inhibit intestinal breast cancer resistance protein and thus increase rosuvastatin plasma exposure 2.1-fold, whereas the OATP-mediated hepatic uptake of rosuvastatin should not be inhibited due to relatively low portal ticagrelor concentrations. Taken together, concomitant use of ticagrelor with rosuvastatin may increase the systemic exposure to rosuvastatin and the risk of rosuvastatin-induced rhabdomyolysis. Further studies are warranted to investigate the potential pharmacokinetic interaction between ticagrelor and rosuvastatin in humans.
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Neoplasias da Mama , Transportadores de Ânions Orgânicos , Rabdomiólise , Estados Unidos , Humanos , Feminino , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinética , Ticagrelor/efeitos adversos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Proteínas de Neoplasias/metabolismo , Interações Medicamentosas , Transportadores de Ânions Orgânicos/metabolismo , Rabdomiólise/induzido quimicamente , Neoplasias da Mama/tratamento farmacológicoRESUMO
BACKGROUND: Salivary bile acids are used to diagnose extraesophageal reflux (EER) and to evaluate the risk of reflux aspiration that is associated with respiratory diseases in dogs. OBJECTIVES: To study total bile acid (TBA) concentrations in saliva and in bronchoalveolar lavage fluid (BALF) to investigate EER and reflux aspiration in dogs with respiratory diseases and in healthy dogs. ANIMALS: Thirty-one West Highland White Terriers (WHWTs) with idiopathic pulmonary fibrosis (IPF), 12 dogs with inflammatory airway disease (IAD), 6 dogs with recurrent pneumonia (RP), 26 brachycephalic dogs (BD), 27 healthy WHWTs (HW), 52 healthy dogs (HD). All privately-owned dogs. METHODS: Saliva and BALF were collected from dogs in each group. RESULTS: Salivary TBA concentrations were higher in IPF (median 0.1692 µM, interquartile range [IQR] 0.1115-0.2925 µM, Cohen's d 3.4, 95% confidence interval [CI] 2.2-4.0, P < .001) and BD (0.0256 µM, IQR 0.0086-0.0417 µM, d 0.5, CI -0.1 to 1.1, P = .003) compared to HD (0 µM, IQR not quantifiable [n.q.]-0.0131 µM). Bronchoalveolar lavage fluid TBA concentrations were higher in IPF (0.0117 µM, IQR 0.0048-0.0361 µM, d 0.5, CI 0-1.1, P < .001) compared to HD (0 µM, IQR n.q.-0.0074 µM). CONCLUSION AND CLINICAL IMPORTANCE: Extraesophageal reflux and reflux aspiration occur in healthy dogs and those with respiratory diseases.
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Doenças do Cão , Refluxo Gastroesofágico , Fibrose Pulmonar Idiopática , Doenças Respiratórias , Cães , Animais , Doenças do Cão/diagnóstico , Fibrose Pulmonar Idiopática/veterinária , Doenças Respiratórias/complicações , Doenças Respiratórias/veterinária , Líquido da Lavagem Broncoalveolar , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/veterinária , Ácidos e Sais BiliaresRESUMO
Drug-drug interactions (DDIs) are a major concern for the safe use of medications. Breast cancer resistance protein (BCRP) is a clinically relevant ATP-binding cassette (ABC) transporter for drug disposition. Inhibition of BCRP increases the plasma concentrations of BCRP substrate drugs, which potentially could lead to adverse drug reactions. The aim of the present study was to identify BCRP inhibitors amongst a library of 232 commonly used drugs and anticancer drugs approved by the United States Food and Drug Administration (FDA). BCRP inhibition studies were carried out using the vesicular transport assay. We found 75 drugs that reduced the relative transport activity of BCRP to less than 25% of the vehicle control and were categorized as strong inhibitors. The concentration required for 50% inhibition (IC50) was determined for 13 strong inhibitors that were previously poorly characterized for BCRP inhibition. The IC50 ranged from 1.1 to 11 µM, with vemurafenib, dabigatran etexilate and everolimus being the strongest inhibitors. According to the drug interaction guidance documents from the FDA and the European Medicines Agency (EMA), in vivo DDI studies are warranted if the theoretical intestinal luminal concentration of a drug exceeds its IC50 by tenfold. Here, the IC50 values for eight of the drugs were 100-fold lower than their theoretical intestinal luminal concentration. Moreover, a mechanistic static model suggested that vemurafenib, bexarotene, dabigatran etexilate, rifapentine, aprepitant, and ivacaftor could almost fully inhibit intestinal BCRP, increasing the exposure of concomitantly administered rosuvastatin over 90%. Therefore, clinical studies are warranted to investigate whether these drugs cause BCRP-mediated DDIs in humans.
Assuntos
Neoplasias da Mama , Dabigatrana , Humanos , Feminino , Preparações Farmacêuticas , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Vemurafenib , Proteínas de Neoplasias/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Interações Medicamentosas , Transporte BiológicoRESUMO
This study aimed to explore the cytochrome P450 (CYP) metabolic and inhibitory profile of hydroxychloroquine (HCQ). Hydroxychloroquine metabolism was studied using human liver microsomes (HLMs) and recombinant CYP enzymes. The inhibitory effects of HCQ and its metabolites on nine CYPs were also determined in HLMs, using an automated substrate cocktail method. Our metabolism data indicated that CYP3A4, CYP2D6, and CYP2C8 are the key enzymes involved in HCQ metabolism. All three CYPs formed the primary metabolites desethylchloroquine (DCQ) and desethylhydroxychloroquine (DHCQ) to various degrees. Although the intrinsic clearance (CLint) value of HCQ depletion by recombinant CYP2D6 was > 10-fold higher than that by CYP3A4 (0.87 versus 0.075 µl/min/pmol), scaling of recombinant CYP CLint to HLM level resulted in almost equal HLM CLint values for CYP2D6 and CYP3A4 (11 and 14 µl/min/mg, respectively). The scaled HLM CLint of CYP2C8 was 5.7 µl/min/mg. Data from HLM experiments with CYP-selective inhibitors also suggested relatively equal roles for CYP2D6 and CYP3A4 in HCQ metabolism, with a smaller contribution by CYP2C8. In CYP inhibition experiments, HCQ, DCQ, DHCQ, and the secondary metabolite didesethylchloroquine were direct CYP2D6 inhibitors, with 50% inhibitory concentration (IC50) values between 18 and 135 µM. HCQ did not inhibit other CYPs. Furthermore, all metabolites were time-dependent CYP3A inhibitors (IC50 shift 2.2-3.4). To conclude, HCQ is metabolized by CYP3A4, CYP2D6, and CYP2C8 in vitro. HCQ and its metabolites are reversible CYP2D6 inhibitors, and HCQ metabolites are time-dependent CYP3A inhibitors. These data can be used to improve physiologically-based pharmacokinetic models and update drug-drug interaction risk estimations for HCQ. SIGNIFICANCE STATEMENT: While CYP2D6, CYP3A4, and CYP2C8 have been shown to mediate chloroquine biotransformation, it appears that the role of CYP enzymes in hydroxychloroquine (HCQ) metabolism has not been studied. In addition, little is known about the CYP inhibitory effects of HCQ. Here, we demonstrate that CYP2D6, CYP3A4, and CYP2C8 are the key enzymes involved in HCQ metabolism. Furthermore, our findings show that HCQ and its metabolites are inhibitors of CYP2D6, which likely explains the previously observed interaction between HCQ and metoprolol.
Assuntos
Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Humanos , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A/metabolismo , Hidroxicloroquina/metabolismo , Hidroxicloroquina/farmacologia , Citocromo P-450 CYP2C8/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores das Enzimas do Citocromo P-450/farmacologia , Microssomos Hepáticos/metabolismoRESUMO
AIMS: The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin. METHODS: We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88). RESULTS: In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10-12 and P = 3.2 × 10-15 ). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P = 4.69 × 10-5 ) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16-62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P = 2.6 × 10-4 ) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P = .01). CONCLUSION: These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.
Assuntos
Estudo de Associação Genômica Ampla , Transportadores de Ânions Orgânicos , Rosuvastatina Cálcica/farmacocinética , Testes Farmacogenômicos , Estudos Prospectivos , Polimorfismo de Nucleotídeo Único , Genótipo , Transportadores de Ânions Orgânicos/genéticaRESUMO
The Pharmacogene Variation Consortium (PharmVar) is now providing star (*) allele nomenclature for the highly polymorphic human SLCO1B1 gene encoding the organic anion transporting polypeptide 1B1 (OATP1B1) drug transporter. Genetic variation within the SLCO1B1 gene locus impacts drug transport, which can lead to altered pharmacokinetic profiles of several commonly prescribed drugs. Variable OATP1B1 function is of particular importance regarding hepatic uptake of statins and the risk of statin-associated musculoskeletal symptoms. To introduce this important drug transporter gene into the PharmVar database and serve as a unified reference of haplotype variation moving forward, an international group of gene experts has performed an extensive review of all published SLCO1B1 star alleles. Previously published star alleles were self-assigned by authors and only loosely followed the star nomenclature system that was first developed for cytochrome P450 genes. This nomenclature system has been standardized by PharmVar and is now applied to other important pharmacogenes such as SLCO1B1. In addition, data from the 1000 Genomes Project and investigator-submitted data were utilized to confirm existing haplotypes, fill knowledge gaps, and/or define novel star alleles. The PharmVar-developed SLCO1B1 nomenclature has been incorporated by the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2022 guideline on statin-associated musculoskeletal symptoms.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Haplótipos , Sistema Enzimático do Citocromo P-450/genética , Alelos , Farmacogenética , Transportador 1 de Ânion Orgânico Específico do Fígado/genéticaRESUMO
Organic Anion Transporting Polypeptide 1B1 is important to the hepatic elimination and distribution of many drugs. If OATP1B1 function is decreased, it can increase plasma exposure of e.g. several statins leading to increased risk of muscle toxicity. First, we examined the impact of three naturally occurring rare variants and the frequent SLCO1B1 c.388A>G variant on in vitro transport activity with cellular uptake assay using two substrates: 2', 7'-dichlorofluorescein (DCF) and rosuvastatin. Secondly, LC-MS/MS based quantitative targeted absolute proteomics measured the OATP1B1 protein abundance in crude membrane fractions of HEK293 cells over-expressing these single nucleotide variants. Additionally, we simulated the effect of impaired OATP1B1 function on rosuvastatin pharmacokinetics to estimate the need for genotype-guided dosing. R57Q impaired DCF and rosuvastatin transport significantly yet did not change protein expression considerably, while N130D and N151S did not alter activity but increased protein expression. R253Q did not change protein expression but reduced DCF uptake and increased rosuvastatin Km. Based on pharmacokinetic simulations, doses of 30 mg (with 50% OATP1B1 function) and 20 mg (with 0% OATP1B1 function) result in plasma exposure similar to 40 mg dose (with 100% OATP1B1 function). Therefore dose reductions might be considered to avoid increased plasma exposure caused by function-impairing OATP1B1 genetic variants, such as R57Q.
Assuntos
Transportadores de Ânions Orgânicos , Espectrometria de Massas em Tandem , Cromatografia Líquida , Células HEK293 , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Transportadores de Ânions Orgânicos/genética , Rosuvastatina CálcicaRESUMO
We investigated genetic determinants of single-dose simvastatin pharmacokinetics in a prospective study of 170 subjects and a retrospective cohort of 59 healthy volunteers. In a microarray-based genomewide association study with the prospective data, the SLCO1B1 c.521T>C (p.Val174Ala, rs4149056) single nucleotide variation showed the strongest, genomewide significant association with the area under the plasma simvastatin acid concentration-time curve (AUC; P = 6.0 × 10-10 ). Meta-analysis with the retrospective cohort strengthened the association (P = 1.6 × 10-17 ). In a stepwise linear regression candidate gene analysis among all 229 participants, SLCO1B1 c.521T>C (P = 1.9 × 10-13 ) and CYP3A4 c.664T>C (p.Ser222Pro, rs55785340, CYP3A4*2, P = 0.023) were associated with increased simvastatin acid AUC. Moreover, the SLCO1B1 c.463C>A (p.Pro155Thr, rs11045819, P = 7.2 × 10-6 ) and c.1929A>C (p.Leu643Phe, rs34671512, P = 5.3 × 10-4 ) variants associated with decreased simvastatin acid AUC. Based on these results and the literature, we classified the volunteers into genotype-predicted OATP1B1 and CYP3A4 phenotype groups. Compared with the normal OATP1B1 function group, simvastatin acid AUC was 273% larger in the poor (90% confidence interval (CI), 137%, 488%; P = 3.1 × 10-6 ), 40% larger in the decreased (90% CI, 8%, 83%; P = 0.036), and 67% smaller in the highly increased function group (90% CI, 46%, 80%; P = 2.4 × 10-4 ). Intermediate CYP3A4 metabolizers (i.e., heterozygous carriers of either CYP3A4*2 or CYP3A4*22 (rs35599367)), had 87% (90% CI, 39%, 152%, P = 6.4 × 10-4 ) larger simvastatin acid AUC than normal metabolizers. These data suggest that in addition to no function SLCO1B1 variants, increased function SLCO1B1 variants and reduced function CYP3A4 variants may affect the pharmacokinetics, efficacy, and safety of simvastatin. Care is warranted if simvastatin is prescribed to patients carrying decreased function SLCO1B1 or CYP3A4 alleles.
Assuntos
Transportadores de Ânions Orgânicos , Sinvastatina , Citocromo P-450 CYP3A/genética , Genótipo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Transportadores de Ânions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Estudos Retrospectivos , Sinvastatina/farmacocinéticaRESUMO
We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.