Human Efflux Transporters in Drug Disposition : in vitro Transport of Glucuronide Metabolites
Year: 2019
Type: dissertation
Abstract: Drug metabolism and transport are key areas in the drug development and therapy. The fate of a drug in the human body is determined by its physicochemical properties, which affect its absorption, distribution, metabolism and elimination processes within the body. The same processes also affect disposition of drug metabolites. Glucuronidation is the most important drug metabolism reaction besides oxidations. Glucuronidation of a drug produces glucuronic acid conjugates that are too hydrophilic to freely permeate cell membranes, and thus they require active transporters for their excretion. Knowledge of disposition of drug metabolites in humans is important for comprehensive understanding of the drug-related effects within the body. For example, glucuronide conjugates of some drugs inhibit drug-metabolizing enzymes and transporters, which causes drug-drug interactions in humans. Therefore, investigations of the molecular mechanisms of drug metabolite excretion are needed. Hepatic and intestinal ATP-dependent efflux transporters multidrug resistance-associated protein 2 (MRP2, ABCC2), MRP3 (ABCC3), MRP4 (ABCC4) and breast cancer resistance protein (BCRP, ACBG2) have been identified to transport glucuronide metabolites of drugs in animal experiments and human in vitro assays. However, systematic studies that compare the properties of these human transporters and characterize their transport kinetics are often lacking. In this thesis, the transport activity of human MRP2-MRP4 and BCRP was evaluated for 18 different glucuronide conjugates of drugs and drug-like compounds, such as androgens and estrogens. The major findings were that MRP2 and MRP3 are rather non-selective transporters and accept most of the glucuronides investigated as their substrates. MRP4 and BCRP, on the other hand, exhibit rather selective transport and these transporters were active only toward some of the glucuronides that were tested in this thesis. P-glycoprotein (P-gp, ABCB1), another important drug efflux transporter, was also included in the assays. However, this transporter did not transport any of the glucuronides investigated. Transport kinetic analyses revealed low Km values for MRP3, mostly clearly below 100 μM. This indicates that MRP3 is a high affinity transporter for glucuronide metabolites in the liver and intestine, where it is highly expressed. The Km values of MRP2 ranged from 120 to 800 μM. These values suggest that MRP2 is a low affinity, but possibly a high capacity, transporter in the same tissues as MRP3. MRP4 and BCRP exhibited Km values between 3-170 μM and 10-80 μM, respectively. In conclusion, MRP2, MRP3, MRP4 and BCRP are important efflux transporters that affect disposition of glucuronide metabolites of drugs in the human body. The affinity of glucuronides to these transporters may determine the different excretion of these drug metabolites in vivo, in either urine or bile.
Source: Työväentutkimus Vuosikirja
Author: Erkka Järvinen
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2997488173