Multi-drug resistance (MDR1) gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs

Abstract

(MDR1) gene expressed in tumor cells and also in several normal tissues, such as intestine, liver, kidney, blood-brain barrier, spinal cord, and placenta. P-gp has been identified in mice, rat, bovine, monkey, rodents, and human beings and has been receiving a particular clinical relevance because this protein expression limits brain access and intestinal absorption of many drugs. This protein plays a role as a protective barrier against a wide variety of substrates, avoiding drug entry into the central nervous system. P-glycoprotein also interferes with drug bioavailability and disposition, including absorption, distribution, metabolization, and excretion, influencing pharmacokinetic and pharmacodynamic of drugs. Modulation of P-gp may help the efficacy of treatment of several diseases and can explain some adverse central nervous system effects induced by drugs after intravenous administration and the poor response of oral administration in patients. Alteration in P-gp expression or function has been associated with several diseases susceptibility in humans and animals. Furthermore, additional studies relating MDR1 and P-gp expression has an important clinical implication also in terms of treatment efficacy.

The Consequence of Drug-Drug Interactions Influencing the Interplay between P-Glycoprotein and Cytochrome P450 3a: An Ex Vivo Study with Rat Precision-Cut Intestinal Slices

“…Also cytochrome P450 3A (CYP3A), a major CYP enzyme, is highly expressed and accounts for metabolism of approximately 50% of therapeutic drugs (Martignoni et al, 2006). The influence of P-gp and CYP3A on the pharmacokinetics and pharmacodynamics of drugs has been widely studied; drug-drug interactions (DDIs) based on their activities are responsible for many unexpected/altered therapeutic effects (Guengerich, 2001;Linardi and Natalini, 2006).…”

Expression of multidrug resistance P-glycoprotein on lymphocytes from nephrotic children treated with cyclosporine A and ACE-inhibitor

“…In our analysis, we also took into account the possible role of ACE-I in the modification of P-gp expression. The data from the literature show that the mechanism of action of this drug is different and ACE-inhibitors are neither P-gp substrates nor inhibitors [12]. Also, the fact that all of the examined children received the same dose of ACE-I during the whole therapy, in contrast to the dose of CyA, which was reduced after 6 months of treatment, may confirm that it is CyA which is responsible for changing the P-gp expression.…”

P-glycoprotein in autoimmune rheumatic diseases

“…Pgp has been identified in canines, rodents, bovine, monkey and human beings [25]. This protein has a structure that comprises a chain of approximately 1280 aminoacid residues [26], with an N-C terminal structure ( Fig.…”

“…Pgp has also been shown to transport hormones from the adrenal gland and the uterine epithelium. Pgp binds and transports through the cell a variety of substrates which are of variable sizes and are mainly hydrophobic with many of them having aromatic rings in their structure (Table 1) [7,21,25].…”