Membrane transport proteins are present in all organisms. These proteins control the influx of essential nutrients and ions and the efflux of cellular waste, environmental toxins, drugs, and other xenobiotics (Figure 4–1). Consistent with their critical roles in cellular homeostasis, about 2000 genes in the human genome, or ~7% of the total number of genes, code for transporters or transporter-related proteins. The functions of membrane transporters may be facilitated (equilibrative, not requiring energy) or active (requiring energy). In considering the transport of drugs, pharmacologists generally focus on transporters from two major superfamilies, ABC and SLC transporters (Nigam, 2015).
Most ABC (ATP binding cassette) proteins are primary active transporters, which rely on ATP hydrolysis to actively pump substrates across membranes. Among the best-recognized transporters in the ABC superfamily are Pgp (encoded by ABCB1, also termed MDR1) and CFTR (encoded by ABCC7).
The SLC (solute carrier) superfamily includes genes that encode facilitated transporters and ion-coupled secondary active transporters. Sixty-five SLC families with about 460 transporters have been identified in the human genome (Pizzagalli et al., 2021). Many SLC transporters serve as drug targets or in drug absorption and disposition. Widely recognized SLC transporters include SERT and DAT, both targets for antidepressant medications.
Abbreviations
ABC: ATP binding cassette
ABCC: ATP binding cassette family C
ACE: angiotensin-converting enzyme
AUC: area under the concentration-time curve
BBB: blood-brain barrier
BCRP: breast cancer resistance protein
BSEP: bile salt export pump
CAR: constitutive androstane receptor
CFTR: cystic fibrosis transmembrane regulator
CLint,all: overall hepatic intrinsic clearance
CLmet: metabolic clearance
CPT-11: irinotecan hydrochloride
Cryo-EM: cryo-electron microscopy
CSF: cerebrospinal fluid
DA: dopamine
DAT: dopamine transporter
FDA: U.S. Food and Drug Administration
FXR: farnesoid X receptor
GABA: γ-aminobutyric acid
GAT: GABA reuptake transporter
GI: gastrointestinal
GLUT: glucose transporter
GSH, GSSG: reduced and oxidized glutathione
HCV: hepatitis C virus
HIV: human immunodeficiency virus
HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A
HNF4α: hepatic nuclear factor 4 alpha
5HT: serotonin
α-KG: α-ketoglutarate
LAT: large amino acid transporter
LeuT: leucine transporter
MAO: monoamine oxidase
MATE1: multidrug and toxin extrusion protein 1
MDMA: 3,4-methylenedioxymethamphetamine
MFS: major facilitator superfamily
MRP: multidrug resistance protein
NBDs: nucleotide-binding domains
NE: norepinephrine
NET: NE transporter
NME: new molecular entity
NTCP: Na+-taurocholate cotransporting polypeptide
OAT1: organic anion transporter 1
OCT1: organic cation transporter 1
OCTN: novel organic cation transporter
OSTα/β: organic solute transporter α/β heterodimer
PAH: p-aminohippurate
PBPK: physiologically based pharmacokinetic
PGE2: prostaglandin E2
Pgp: P-glycoprotein
PPARα: peroxisome proliferator-activated receptor α
PXR: pregnane X receptor
RAR: retinoic acid receptor
RFC: reduced folate carrier
RXR: retinoid ...