Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

Abstract

The kidneys are a pair of important organs that excretes endogenous waste and exogenous biological agents from the body. Numerous transporters are involved in the excretion process. The levels of these transporters could affect the pharmacokinetics of many drugs, such as organic anion drugs, organic cationic drugs, and peptide drugs. Eleven drug transporters in the kidney (OAT1, OAT3, OATP4C1, OCT2, MDR1, BCRP, MATE1, MATE2-K, OAT4, MRP2, and MRP4) have become necessary research items in the development of innovative drugs. However, the levels of these transporters vary between different species, sex-genders, ages, and disease statuses, which may lead to different pharmacokinetics of drugs. Here, we review the differences of the important transports in the mentioned conditions, in order to help clinicians to improve clinical prescriptions for patients. To predict drug-drug interactions (DDIs) caused by renal drug transporters, the molecular docking method is used for rapid screening of substrates or inhibitors of the drug transporters. Here, we review a large number of natural products that represent potential substrates and/or inhibitors of transporters by the molecular docking method.

[11C]glyburide PET imaging for quantitative determination of the importance of Organic Anion-Transporting Polypeptide transporter function in the human liver and whole-body

“…In this situation, a competition may occur between influx and efflux transporters at the same interface [14]. The role of OATPs expressed in the kidneys such as OATP4C1 is poorly understood [52]. Given the high proportion of radiometabolites in urine, the radio-HPLC analysis of urine samples was not sensitive enough to detect the excreted amount of parent (unmetabolized) [ 11 C] glyburide at the end of PET acquisition.…”

Interplay of Breast Cancer Resistance Protein (Bcrp/Abcg2), Sex, and Fed State in Oral Pharmacokinetic Variability of Furosemide in Rats

“…Similar to humans, Bcrp expression in rats is abundant in the intestinal segments, but only rat kidneys express Bcrp to a detectable level. For example, the levels of Bcrp in rat and human kidney are 4.5 pmol/mg protein and below limit of quantification (0.09 pmol/mg protein), respectively [ 23 , 27 , 28 , 29 ]. This suggests that the effect of Bcrp inhibition on the bioavailability of its substrates can be investigated using the rat model; however, rat is not a good species for translating renal elimination of Bcrp substrates.…”

Immunohistochemical Localization of Alogliptin, a DPP-4 Inhibitor, in Tissues of Normal and Type 2 Diabetes Model Rat

“…As AG is a cationic drug with a small molecular weight, it easily passes through the basement membrane, and most of it is filtered into primary urine. Among the reabsorption transporters present on the apical side of proximal tubular epithelial cells, PEPTs do not use AG as a substrate and OAT2 and OAT4 could possibly use AG as a substrate, but OAT4 is not expressed in rats [21,29].…”

“…Excretory transporters such as P-gp, MRP2, MRP4, and BCRP are expressed on the apical side of the proximal tubular epithelial cells [2,8,29]. P-gp is also expressed in distal tubules and collecting ducts [7,10].…”