Does inhibition of P-glycoprotein lead to drug–drug interactions?

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…164,165 Itraconazole Substrate for CYP3A4; 57 potent inhibitor of CYP3A4 160 and less so for CYP2C9, CYP2C19. 45 Substrate 166 and inhibitor of P-gp. 160,161,167 Conflicting data as to inhibitory effect on OATP.…”

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…These evolutionary highly conserved multispan transmembrane molecules use the energy of ATP hydrolysis to translocate a broad spectrum of molecules across the cell membrane. To date, 48 members of the human family of ABC transporters have been identified which, based on their structural relatedness, are subdivided into seven families, designed ABC A-G. [53][54][55][56][57][58]. These ABC transporters participate in diverse cellular processes, including drug resistance and metabolism, transport of lipids and organic anions, and iron metabolism [54,55].…”

“…Membrane-associated ABC transporters have been found in two forms, the full-length transporters that are characterized by two identical halves each containing the NBD and the half-transporters that function as homo-or heterodimers ( Figure 1) [53][54][55]64]. As one of the best studied ABC transporters, the multidrug resistance (MDR1) P-glycoprotein (P-gp), also known as ABCB1, is a glycosylated membrane-associated enzyme 860 npg of the full-length form comprising 1 280 amino acids (with a molecular weight of 170 kDa), and is characterized by two identical halves, each with one NBD; it exports a wide range of diverse substrates [54,55,57]. Another member of the ABC transporter family that is intensively studied is ABCG2 (also known as MXR/BCRP1/ABCP), which is a half-transporter and requires dimerization for its functional activity [65,66].…”

“…In addition to being important export pumps for physiological substances, MRP subfamily members are involved in the active efflux of toxic organic anions [78][79][80][81][82]. MRP transporters have been shown to confer resistance to harmful drugs, possibly by the above-mentioned ATP-dependent export of such molecules [54][55][56][57].…”

“…ABCB1 is widely expressed in normal tissues with excretory functions such as the liver, kidney and intestine, and is also involved in barrier functions such as in the blood-brain barrier (BBB) and the blood-testis barrier [54,57,84,85]. Apart from being induced by chemotherapeutic drugs, ABCB1 expression and upregulation of its activity have been observed in primary rat hepatocyte culture by EGF [86].…”