Table V.

Most Important Membrane Transporters for Brain Drug Delivery. The Data Have Been Collected from Uniprot Proteome Databases and the Database Mentioned in the Reference (82), Unless Otherwise Stated

		Gene name(s)	Endo-genous substrate(s)	Main Physiological role	Drug substrates / inhibitors(#)	Expression at the Brain barriers
						BBB	BSCB	BCSFB	BAB
Efflux transporters	ABCs	ABCA2	Lipid (cholesterol)	Sphingolipid homeostasis - Cholesterol homeostasis – Transport across the BBB	–	+ (a)
		ABCA8	Tauro-cholate and estrone sulphate	Sphingomyelin production – Lipid transport - Cholesterol homeostasis	–	+ (a)	+ (b)	+ (c)
		ABCB1 (MDR1)	Phospho-lipids	Xenobiotic transport across blood-brain barrier - Phospholipid translocation	Verapamil, Saquinavir, Reserpine, Nifedipine, Mifepristone, Dexamethasone, Digoxin, Trimethoprim, Progesterone, Tacrolimus, Phenobarbital, Tamoxifen, Asciminib, Octreotide, Temozolomide, Lamotrigine	+ (a)	+ (b)	+ (c)	+p (d)
		ABCC1 (MRP1)	GSH, leukotriene C4, estradiol glucuronide	GSH transport - Leukotriene metabolic process - Cobalamin transport	Grepafloxacin, Saquinavir, Dactinomycin, Zoledronic acid, Atorvastatin, Saxagliptin, Acemetacin, Prasterone			+ (c)
		ABCC2 (MRP2)	glucuronideand GSH conjugates	transport across blood-brain barrier – transport of thyroid hormone, leukotriene and bil acids	Vincristine, Methotrexate, Saquinavir, Ritonavir and Indinavir	+ (e)
		ABCC3 (MRP3)	Bilirubin di-glucuronide, Estradiol glucuronide, GSH conjugates	Canalicular bile acid transport – Leukotriene transport	Gadoxetic acid, Ezetimibe, Raloxifene, Fexofenadine, Methotrexate, Etoposide, Lamivudine, Fluorouracil				+p (d)
		ABCC4 (MRP4)	cAMP, cGMP, Bile acids, Steroids, GSH, Prosta-glandins	Xenobiotic transport across blood-brain barrier - Cellular communication and signalling – Prostaglandin and GSH transport	GSH, Dinoprostone, Atorvastatin, Oseltamivir, Alprostadil, Cefazolin, Nateglinide, Fluorouracil, Raloxifene, Prasterone	+ (a)		+ (c)
		ABCC8		Regulation of insulin secretion - Potassium ion transport		+ (a)
		ABCG2 (BCRP)	Wide variety of physiological compounds e.g., protopor-phyrin IX, sphingosine-1-P	Xenobiotic transport across blood-brain barrier – Biotin transport – Cellular detoxification – Heme biosynthetic process	Topotecan, Glyburide, Pravastatin, Doxorubicin, Mitoxantrone, Prazosin, Etoposide, Cerivastatin, Tamoxifen, Sumatriptan, Alvocidib, Ivermectin, Oxaliplatin, Leflunomide, Mycophenolate mofetil	+ (a)	+ (b)	+ (c)	+p (d)
Organic anion transporting polypeptides	OATPs	SLCO 1A2 (OATP 1A2)	Conjugated and unconjugated bile acids	Recycling of bile acids and salts	Pravastatin, Enalapril, Rocuronium, Budesonide, Levofloxacin, Indomethacin, Deoxycholic acid, Fexofenadine	+
		SLCO 2B1 (OATP 2B1)	Prosta-glandins (PGD2, PGE1, PGE2), leukotriene C4, thrombo-xane B2 and iloprost	Recycling of bile acids and salts - Heme catabolic process	Tolbutamide, Ibuprofen, Salicylic acid, Montelukast, Simeprevir Opicapone, Pravastatin, Dinoprostone, Fexofenadine	+			+p (d)
		SLCO 3A1 (OATP 3A1)	Estrone-3-sulfate, PGE1, PGE2, vasopressin, thyroxine	Transport across the BBB - Prostaglandin transport	Safinamide, Dinoprostone, Methotrexate, Iloprost, Conjugated estrogens, Alprostadil#			+ (c)
		Other potential members such as SLCO1A1, SLCO1A4, SLCO1C1, SLCO1B1, SLCO1B3, SLCO1B7, SLCO2A1, SLCO4A1, SLCO4C1, SLCO5A1 & SLCO6A1
Organic anion transporters	OATs	SLC 22A6 (OAT1)	Glutarate	Alpha-ketoglutarate transport - Renal tubular secretion	Didanosine, Famotidine, Probenecid, Lamivudine, Latanoprost, Furosemide				+p (d)
		SLC 22A8 (OAT3)	Estrone 3-sulfate	Excretion/ detoxification of endogenous and exogenous organic anions in brain and kidney	Valaciclovir, Oseltamivir, Saxagliptin, Allopurinol, Avibactam, Cefdinir, Edaravone, Sitagliptin, Budesonide, Ibuprofen#, Indomethacin#, Diclofenac#			+ (c)	+p (d)
Organic cation transport	OCTs	SLC 22A2 (OCT2)	Dopamine, nor-adrenaline, serotonin, choline	Transport across the BBB - Neurotransmitter clearance	Dalfampridine, Dofetilide, Terbutaline, Histamine, Amantadine, Metformin, Memantine, Pramipexole, Reserpine, Lamivudine, Amiloride#, Amiodarone#				+p (d)
Multidrug and toxin extrusion	MATEs	SLC 47A1 (MATE1)	Estrone sulfate	Secretion of cationic drugs - Transport of bile salts and organic acids	Cefradine, Metformin, Cimetidine, Cephalexin, Acyclovir, Ganciclovir Abemaciclib, Brigatinib, Relebactam, Fosdenopterin,, Famotidine#, Verapamil#			+ (c)	+p (d)
Amino acid transporters	EAATs	SLC1A3 (EAAT1)	L-Glu, L-Asp & D-Asp	Glutamate synaptic transmission	Glu and Asp analogues	+ (a)	+ (b)	+ (c)
		SLC1A2 (EAAT2)				+ (b)	+ (b)
	ASCTs	SLC1A4 (ASCT1)	Ala, Ser, Cys and Thr	D-Ser synaptic transmission	–	+
		SLC1A5 (ASCT2)	Broad substrate specificity	Nutritional and developmental functions	Fluciclovine (18F), Serine conjugates	+ (a)
	NAT	SLC 6A12 (BGT1)	Betaine and GABA	GABAergic transmission	Guvacine#	+ (a)
	CATs	SLC7A1 (CAT1)	Cationic AAs (Arg, Lys and Orn)	Transport of Arg - Signalling pathways such as mTORC and activation of macrophages	–	+ (a)		+ (c)
	HATs	SLC7A5 (LAT1)	Large neutral AAs.	Activation of mTOR signalling pathways – transport of thyroid hormones	Levodopa, Pregabalin, Baclofen, Gapepentin	+ (a)
		SLC7A11 (xCT)	Cys, Glu	Regulation of Cys and Glu metabolic processes	Sulfasalazine#, Thimerosal#				+p (d)
	SNATs	SLC 38A2 (SNAT2)	Small neutral AAs (L-Ala, L-Cys, L-Ser, L-His, L-Gln and L-Met)	Transport AAs across the BBB and placental barrier – Glutamate Neurotransmitter Cycle	–	+			+
		SLC 38A3 (SNAT3)	Gln, His, Asn, Ala	Regulation of Gln/Glu cycle - Nutritional and developmental functions	–	+ (b)	+ (b)
	PEPT	SLC 15A2 (PEPT2)	Oligo-peptides & Dipeptides	Transport across BBB – Innate immune response	Quinapril, Ubenimex, Valaciclovir, Bestatin, Cefadroxil, Amoxicillin#, Chlorpropamide#				+p (d)
Monocarboxylate transporters	MCTs	SLC 16A1 (MCT1)	Lactate, pyruvate, branched chain oxo acids	Pyruvate metabolic process - glucose homeostasis – Transport across BBB	Salicylic acid, Foscarnet, Pravastatin, Probenecid#, Niflumic acid#	+ (a)	+ (b)	+ (c)	+p (d)
		SLC 16A3 (MCT4)			α-Ketoisovalerate, Oxamic Acid, Pyruvic acid			+ (c)	+
		SLC 16A4 (MCT5)			–			+ (c)
		SLC 16A2 (MCT8)	Thyroid hormone transporter	Transport across the BBB - Thyroid hormone metabolic process	Leucine, Thyroid-Porcine, Levothyroxine#, Liotrix#	+ (b)	+ (b)	+ (c)	+p (d)
Glucose transporter	GLUTs	SLC2A1 (GLUT1)	Glucose, aldoses	Most important energy carrier of the brain - Promotes retinal cone survival	Fludeoxyglucose (18F), Glucosamine, Resveratrol, Ascorbic acid, Butabarbital#, Etomidate#	+ (a)	+ (b)	+ (c)	+p (d)
Other influx transporters		SLC5A6 (SMVT)	Panto-thenate, biotin and lipoate	Vitamin transporter activity – Transport across the BBB	Gabapentin enacarbil, Biotin	+ (b)	+ (b)
		SLC 29A1 (ENT1)	Nucleosides (adenosine)	Nucleoside and neurotransmitter transport	Cytarabine, Fludarabine, Gemcitabine, Ribavirin, Fluorouracil, Cannabidiol#, Troglitazone#	+ (a)		+ (c)
		SLC 29A4 (PMAT)	Monoamine neurotransmitt-ers	Neurotransmitter transport – Transport across the BBB	Metformin, Adenosine			+ (c)
		SLC 44A1 (CTL1)	Choline	Membrane synthesis and myelin production – Transport across the BBB	Choline salicylate	+ (b)	+ (b)
		SLC 44A2 (CTL2)				+ (b)	+ (b)
		SLC6A8 (CRT1)	Creatine	Creatine metabolic process	–	+		+ (c)
		SLC 19A1 (RFC1)	Reduced folates	Folate transport – Transport across the BBB	Pralatrexate, Methotrexate, Levomefolic acid, Trimetrexate	+ (a)
		SLC 27A1 (FATP1)	long-chain fatty acids (LCFA)	Transport of fatty acids – Cell signaling – Transport across the BBB	–	+

BBB, Blood-brain barrier; BSCB, Blood spinal cord barrier; BCSFB, Blood-cerebrospinal fluid barrier; BAB, Blood-arachnoid Barrier; AAs, Amino acids; GSH, Glutathione; L-Glu, L-Glutamate; L-Asp, L-Aspartate; D-Asp, D-Aspartate; Ala, Alanine; Ser, Serine; Cys, Cysteine; Thr, Threonine; Arg, Arginine; Lys, Lysine; Orn, Ornithine; L-His, L-Histidine; L-Gln, L-Glutamine; L-Met, L-Methionine; Asn, Asparagine; p, pig

^#refers to inhibitors; (a) data obtained from the reference (9); (b) data obtained from the reference (5); (c) data obtained from the reference (66); (d) data obtained from the reference (36); (e) data obtained from the reference (46)