RESUMEN
With the widespread clinical use of drug combinations, the incidence of drug-drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.
Asunto(s)
Proteínas de Transporte de Anión/farmacocinética , Enfermedades Renales/tratamiento farmacológico , Transportadores de Anión Orgánico/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Animales , Proteínas de Transporte de Anión/farmacología , Transporte Biológico , China , Creatinina/metabolismo , Interacciones Farmacológicas , Fibrosis , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/metabolismo , Fallo Renal Crónico/patología , Masculino , Transportadores de Anión Orgánico/farmacología , Proteínas de Transporte de Catión Orgánico/genética , Preparaciones Farmacéuticas/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
About 30% of approved drugs are cleared predominantly by renal clearance (CLr). Of these, many are secreted by transporters. For these drugs, in vitro-to-in vivo extrapolation of transporter-mediated renal secretory clearance (CLsec,plasma) is important to prospectively predict their renal clearance and to assess the impact of drug-drug interactions and pharmacogenetics on their pharmacokinetics. Here we compared the ability of the relative expression factor (REF) and the relative activity factor (RAF) approaches to quantitatively predict the in vivo CLsec,plasma of 26 organic anion transporter (OAT) substrates assuming that OAT-mediated uptake is the rate-determining step in the CLsec,plasma of the drugs. The REF approach requires protein quantification of each transporter in the tissue (e.g., kidney) and transporter-expressing cells, whereas the RAF approach requires the use of a transporter-selective probe substrate (both in vitro and in vivo) for each transporter of interest. For the REF approach, 50% and 69% of the CLsec,plasma predictions were within 2- and 3-fold of the observed values, respectively; the corresponding values for the RAF approach were 65% and 81%. We found no significant difference between the two approaches in their predictive capability (as measured by accuracy and bias) of the CLsec,plasma or CLr of OAT drugs. We recommend that the REF and RAF approaches can be used interchangeably to predict OAT-mediated CLsec,plasma Further research is warranted to evaluate the ability of the REF or RAF approach to predict CLsec,plasma of drugs when uptake is not the rate-determining step. SIGNIFICANCE STATEMENT: This is the first direct comparison of the relative expression factor (REF) and relative activity factor (RAF) approaches to predict transporter-mediated renal clearance (CLr). The RAF, but not REF, approach requires transporter-selective probes and that the basolateral uptake is the rate-determining step in the CLr of drugs. Given that there is no difference in predictive capability of the REF and RAF approach for organic anion transporter-mediated CLr, the REF approach should be explored further to assess its ability to predict CLr when basolateral uptake is not the sole rate-determining step.
Asunto(s)
Vías de Eliminación de Fármacos/fisiología , Interacciones Farmacológicas , Transportadores de Anión Orgánico , Eliminación Renal/efectos de los fármacos , Transporte Biológico/fisiología , Desarrollo de Medicamentos , Evaluación Preclínica de Medicamentos/métodos , Humanos , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/farmacocinética , Preparaciones Farmacéuticas/metabolismo , Farmacocinética , Valor Predictivo de las PruebasRESUMEN
BACKGROUND: Enhanced drug elimination in alcoholics remains largely indefinable. In contrast, the reduced elimination of drugs in patients with advanced alcoholic liver disease (ALD) is normally owing to hepatic end-stage disease such as cirrhosis. We here study the mRNA expression of various hepatic drug metabolizing enzymes and transporters in association with liver stiffness (LS) being a novel noninvasive parameter for the assessment of cirrhosis to unravel the dynamic relationship between ALD and determinants of pharmacokinetics such as drug metabolizing enzymes and transporters. METHODS: We quantified mRNA expression levels of various cytochrome P-450 isoenzymes (CYPs) and drug transporters in 26 liver specimens of chronic alcoholics and 5 controls by quantitative polymerase chain reaction. In addition, liver histology, clinical data, and LS evaluated by transient elastography (Fibroscan) were obtained. RESULTS: Eighteen patients had a normal or moderate LS < 8 kPa (69.2%), while in the remaining 8 patients (30.7%) advanced F3 or F4 fibrosis could be established with an LS > 8 kPa. Overall, CYP3A4, CYP2E1, and solute carrier organic anion transporter 1B1 (SLCO1B1) were negatively correlated with increasing LS. CYPs and drug transporters tended to be up-regulated in alcoholics without advanced fibrosis (LS < 8.0 kPa) compared to healthy controls supporting data of boosted drug elimination in alcoholics without advanced ALD. However, in alcoholics with severely increased LS (>8 kPa), expression levels of CYP2E1, SLC22A2, and SLCO1B1 were significantly lower. CONCLUSIONS: In conclusion, CYPs and drug transporters seem to be induced in chronic alcoholics without irreversible liver damage but decline in case of manifest cirrhosis. Our study also suggests that noninvasive measurements of LS could be useful for pharmacokinetic predictions and individualized pharmacotherapy.
Asunto(s)
Sistema Enzimático del Citocromo P-450/farmacocinética , Cirrosis Hepática/metabolismo , Hepatopatías Alcohólicas/metabolismo , Hígado/metabolismo , Transportadores de Anión Orgánico/farmacocinética , Adulto , Sistema Enzimático del Citocromo P-450/biosíntesis , Sistema Enzimático del Citocromo P-450/genética , Diagnóstico por Imagen de Elasticidad/métodos , Femenino , Regulación de la Expresión Génica , Humanos , Hígado/patología , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Hepatopatías Alcohólicas/genética , Hepatopatías Alcohólicas/patología , Masculino , Persona de Mediana Edad , Transportadores de Anión Orgánico/biosíntesis , Transportadores de Anión Orgánico/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , ARN Mensajero/farmacocinéticaRESUMEN
Drugs and their metabolites are eliminated mainly by excretion into urine and bile. Studies in whole animals, isolated organs, cells, and membrane vesicles led to the conclusion that different transport systems are responsible for the transport of different classes of organic compounds (small, large, anionic, and cationic). In the early 1990s, functional expression cloning resulted in the identification of the first transporters for organic anions and cations. Eventually, all the major transport systems involved in the uptake of these organic compounds were cloned and characterized, and we now know that they belong to the organic anion transporters (OATs) and organic cation transporters (OCTs) of the SLC22A superfamily and the organic anion-transporting polypeptides (OATPs) of the SLCO superfamily of polyspecific drug transporters. Today we can explain, at the molecular level, why small and hydrophilic organic compounds are excreted predominantly through urine whereas large and amphipathic compounds are excreted mainly through bile, and we can start to predict drug-drug interactions in the case of new compounds.