Mini-reviewDoes inhibition of P-glycoprotein lead to drug–drug interactions?
Introduction
“The more drugs a patient takes, the greater the likelihood that an adverse reaction will occur” (Stockley, 1999). Rate of drug–drug interactions in common clinical practices varies from 0% to 50%, according to patients (state of health, age, etc.), drugs (pharmacokinetic and pharmacodynamic) and prescriptions (hospital and ambulatory). Drug–drug interactions are of two types: pharmacokinetic or pharmacodynamic, but adverse events are generally linked to the association of drugs able to induce or inhibit drug metabolising enzymes and drugs with a narrow therapeutic window (Stockley, 1999).
The efflux proteins of the multidrug resistance (MDR) are known to be implied in the transport of many xenobiotics out of cells (Stouch and Gudmundsson, 2002). Among these transporters, permeability-glycoprotein (Pgp) is particularly studied in the field of oncology, because it represents a significant factor of chemoresistance (List, 1996, Billson et al., 1994). Pgp modulates the drug pharmacokinetics and remains poorly evaluated for drug–drug interactions. Nevertheless, for example, out of 66 drugs representing 8 pharmacological classes, 18 used at clinical therapeutic doses and 10 other molecules at slightly superior doses are able to modify the cellular accumulation of daunomycin following a Pgp inhibition on culture cells (Ibrahim et al., 2000, Ibrahim et al., 2001).
Importance of Pgp in the pharmacokinetics of numerous drugs becomes more and more evident (Stouch and Gudmundsson, 2002) and their potential roles for drug–drug interactions are just beginning to be realised (Yu, 1999).
In this review, we evaluate the involvement of Pgp in terms of drug–drug interactions and drug toxicity. After a short description of the efflux protein, Pgp, the discussion will be focused on two important pharmacokinetic phases, absorption/excretion and distribution, that are under the influence of this transporter.
Section snippets
P-glycoprotein (Pgp)
Permeability-glycoprotein belongs to the ABC transporter superfamily. These transporters correspond to a wide range of proteins able to hydrolyse ATP, also named ATP binding cassette (ABC). Pgp was first described by Juliano and Ling (1976) and is the product of the MDR1 gene in humans and mdr1a and mdr1b genes in rodents (Barrand et al., 1995, Johnson et al., 2001). Pgp is a transmembrane protein of 170 kDa, formed by two homologous halves working as an efflux pump ATP-dependent, localised on
Absorption and excretion
Pgp is found on the different barriers that limit the passage of xenobiotics into the organism. Pgp is described as an important mechanism decreasing the bioavailability of oral drugs by limiting intestinal absorption (Aungst, 1999, Suzuki and Sugiyama, 2000, Napoli et al., 1998). Moreover, Pgp can directly eluate drugs from the general circulation into the bile and intestinal lumen via hepatocytes and enterocytes, respectively (Sparreboom et al., 1997, Schinkel and Jonker, 2003). Thus it can
Conclusion
Pgp is involved in the pharmacokinetics of numerous drugs. With regard to the pharmacokinetic law: ADME (absorption, distribution, metabolism and elimination), these efflux proteins participate in the absorption, distribution and elimination phases, contrary to cytochrome P450 enzymes that are only involved in drug metabolism. The importance of Pgp is linked to its distribution in the body: on one hand in the intestine, liver and kidneys and on the other hand in blood–tissue barriers. In
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