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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).

Figure 4–1

Membrane transporters in pharmacokinetic pathways. Membrane transporters (T) play roles in pharmacokinetic pathways (drug absorption, distribution, metabolism, and excretion), thereby setting systemic drug levels. Drug levels often drive therapeutic and adverse drug effects.

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.



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 ...

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