Table II.
(Pro)drugs Developed to Utilize SLC Transporters for Improvement of Brain Delivery of Drugs
| (Pro)drug | Investigation of prodrug activity | Evidence of utilization of specific transporter | Information about the BBB permeation and extent of brain delivery | Information about intra-brain distribution | In vivo pharmacodynamic evidence | Clinical evidence |
|---|---|---|---|---|---|---|
| LAT1 | ||||||
| Isoleucinyl ester of the 5’-hydroxyl group of zidovudine (105, 106) | Similar or more potent in inhibiting the viral replication in vitro compared to parent drug | NR | In vivo PK study in rabbits: after i.v. injection of 18 mg/kg prodrug C30min,total,brain/C30min,total,plasma of released parent drug at was same compared to parent drug dosing (10 mg/kg), C75min,total,brain/C75min,total,plasma of released parent drug was twice higher compared to parent drug dosing | NR | NR | NR |
| L-4-chlorokynurenine (4-Cl-KYN), a prodrug of 7-chlorokynurenic acid (107, 108) | NR |
In situ brain perfusion in rats: saturated BBB uptake Vmax 16.9 ± 2.3 nmol/min/g and Km of 105 ± 14 µM 4-Cl-KYN reduced L-[14C]leucine uptake to the brain in a concentration-dependent manner (Ki 116 ± 10 µM) |
In situ brain perfusion in rats: 4-Cl-KYN crossed the BBB and released parent drug 20 s after perfusion with 100 µM or 500 µM prodrug Cerebral microdialysis study in rats: release of parent drug in hippocampus within 1 h after prodrug administration with increased release until a steady state was reached at about 3 h |
NR | NR | NR |
| Tyrosine prodrug of nipecotic acid (109) | NR | NR | NR | NR | In vivo study in genetically seizure-prone strain (DBA/2) of mice: prodrug showed significant dose-dependent anticonvulsant activity after i.p. injection, while parent drug had no anticonvulsant effect | NR |
| L-cysteine conjugate of 2-methyl-1-propanethiol (110) | NR |
In situ brain perfusion in rats: prodrug inhibited [14C]L-leucine brain uptake by 92% Prodrug Ki of [14C]L-leucine uptake in different brain regions ranged 6.9–12.8 µM |
NR | NR | NR | NR |
| L-cysteine conjugate of 6-mercaptopurine (110) | NR | In situ brain perfusion in rats: prodrug inhibited [14C]L-leucine uptake by 63% | NR | NR | NR | NR |
| L-tyrosine prodrug of ketoprofen (111) | NR |
In situ brain perfusion in rats: prodrug inhibited [14C]L-leucine brain uptake by 98% Prodrug brain uptake Km was 22.5 ± 9.18 μM and Vmax = 1.4 ± 0.15 pmol/mg/min Prodrug brain uptake was significantly inhibited by BCH |
In situ brain perfusion in rats: prodrug crossed BBB, the concentration of prodrug in the endothelial cell-enriched pellet fraction was below the lower limit of detection | NR | NR | NR |
| Lysine derivative of ketoprofen (79, 112–114) | Active prodrugs, as demonstrated by inhibition of COX peroxidase activity in vitro (IC50 1.05 µM) |
In situ rat brain perfusion: prodrug inhibited [14C]L-leucine brain uptake by 79%, prodrug brain uptake Km 231.6 ± 60.4 μM and Vmax 1.50 ± 0.20 pmol/mg/min, brain uptake of prodrug was significantly inhibited by L-phenylalanine In vitro uptake study: In ARPE19 cells Km 6.9 μM and Vmax 11.1 pmol/min/mg protein Prodrug inhibited [14C]L-leucine uptake by 17.6% Prodrug uptake was inhibited by LAT1 inhibitor by 61.5% |
In situ brain perfusion in mice: BBB rate of permeation Kin 0.06 Cerebra microdialysis study in rats: Kp,uu,brain prodrug 0.09 Kp,uu,brain ketoprofen 0.12 Kp,uu,brain released ketoprofen 0.33 In vivo PK study in mice: AUCu,brain/AUCu,plasma 0.016 after a single dose of 25 μmol/kg i.p, no detected parent drug in the brain |
Cerebral microdialysis study in rats: Kp,uu,cell of prodrug 1.2, while for parent drug—0.47 Kp,uu,cell for released parent drug—63.6 Cerebral microdialysis study in mice: Kp,uu,cell of prodrug 0.03, while for parent drug – not determined (lower detection limit) Kp,uu,cell for released parent drug—63.6 |
NR | NR |
| Ester-based meta- and para-substituted phenylalanine prodrugs of valproic acid (115, 116) | NR |
In situ brain perfusion in rats: prodrugs inhibited [14C]L-leucine brain uptake (Ki of meta- and para-substituted prodrugs 2.7 μM, and 32.4 μM, respectively), In vitro uptake in MCF7 cells: no detectable uptake of prodrugs, prodrugs inhibited 78% and 46% of [14C]L-leucine, respectively |
In situ brain perfusion in rats: the BBB permeation rate of prodrugs (600 μM) was 4.7 and 3.1 pmol/mg/min, respectively |
NR | NR | NR |
| Amide-based meta- and para-substituted phenylalanine prodrugs of valproic acid (115, 116) | NR |
In situ brain perfusion in rats: prodrugs inhibited [14C]L-leucine brain uptake (Ki of meta- and para-substituted prodrugs 3.2 μM, and 34.1 μM, respectively), In vitro uptake in MCF7 cells: prodrugs inhibited 81% and 48% of [14C]L-leucine, respectively Cellular uptake for meta- and para-substituted prodrugs were ca 28 pmol/min/mg protein |
In vivo PK study in rats: after i.v. bolus injection of 40 μmol/kg of meta-substituted prodrug Kp,brain prodrug 0.069 Kp,brain of released parent drug from prodrug 0.056, after i.v. bolus injection of 40 μmol/kg of para-substituted prodrug Kp,brain prodrug 0.039, no detected parent drug in the brain Kp,brain parent drug dosing 0.048 In situ brain perfusion in rats: the BBB permeation rate of prodrugs (600 μM) was 28.9 and 12.2 pmol/mg/min, respectively |
NR | NR | NR |
| Amide-based para-substituted phenylalanine prodrug of valproic acid with additional methylene linker (115) | NR | In vitro uptake in MCF7 cells: prodrug inhibited 89% of [14C]L-leucine Cellular uptake of prodrug was 48 pmol/min/mg of protein |
In vivo PK study in rats: after i.v. bolus injection of 40 μmol/kg prodrug Kp,brain prodrug 0.24 and Kp,brain released parent drug 0.3 while for parent drug Kp,brain 0.048 |
NR | NR | NR |
| L-lysine-methotrexate conjugate (117) | NR | NR |
In vivo PK study in mice: after i.v. injection 7.15 mM/kg of prodrug or parent drug Kp,brain released parent drug 0.34 Kp,brain parent drug 0.08 AUCtotal,brain of released parent drug was 7.74 times higher after prodrug dosing compared to parent drug itself |
NR | NR | NR |
| Aspartic acid prodrug of dopamine and 2-amino-apidic acid prodrug of dopamine (118) | NR | In situ brain perfusion in rats: 35–38% inhibition of [14C]L-leucine brain uptake by prodrugs |
In situ brain perfusion in rats (only 2-amino-apidic acid prodrug of dopamine): Prodrug was not detected in the brain after perfusion |
NR | NR | NR |
| Meta-conjugated phenylalanine prodrug of dopamine (118, 119) | NR |
In situ brain perfusion in rats: 85% inhibition of [14C]L-leucine brain uptake by prodrugs, the BBB uptake Km 227 μM and Vmax 0.99 pmol/mg/min Prodrug brain uptake was inhibited by 61% by L-phenylalanine In vitro study in MCF7 cells: concentration-dependent inhibition of [14C]L-leucine cellular uptake by prodrug (12.5–100 μM) |
In situ brain perfusion in rats: prodrug crossed BBB after perfusion In vivo PK study in rats: after i.p. injection of prodrug Kp,brain prodrug 0.009, no improvement of dopamine levels in brain after prodrug administration compared to L-dopa or control animals |
NR | NR | NR |
| L-tyrosine carbamate prodrug of dopamine (119) | NR | In vitro study in MCF7 cells: prodrug inhibited [14C]L-leucine cellular uptake. IC50 was calculated with four concentrations of prodrug | NR | NR | NR | NR |
| Ester-based and amide-based prodrugs of perforin inhibitors (120–123) | NR |
In situ brain perfusion in mice: 97% and 59% inhibition of [14C]L-leucine brain uptake by ester-and amine-based prodrugs, respectively Brain uptake of ester-based prodrug was inhibited by co-treatment of probenecid and L-tryptophan, brain uptake amide-based prodrug was inhibited by probenecid alone and probenecid plus L-tryptophan In vitro study in MCF7 cells: ester-based prodrug Km 37 µM and Vmax 10 nmol/mg/min Amide-based prodrug Km 13 µM and Vmax 0.60 nmol/mg/min In astrocytes: [14C]L-leucine brain uptake inhibition by ester-based prodrug (IC50 3.5 μM), not saturable uptake at 1–200 μM prodrug |
In vivo PK study in mice: after i.p. bolus injection of 23 μmol/kg ester- and amide-based prodrugs i.p. in mice Kp,brain ester-based prodrug was 0.043, Kp,brain amide-based prodrug was 0.035 Released parent drug was detected only after ester-based prodrug dosing Parent drugs itself were not detected in the brain after the dosing |
In vitro study in mouse cortical astrocytes and cortical neurons: improved uptake of prodrugs in mouse astrocytes and neurons compared to parent drugs In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: Concentration-dependent uptake in mouse primary neurons, astrocytes, and microglia at concentration 25, 50, 100 μM |
In vivo study in LPS-induced inflammation mouse model: no improvement of reduction of prostaglandin E2 levels in the brain after prodrug dosing compared to parent drug dosing |
NR |
| Meta-conjugated phenylalanine derivative of ketoprofen (79, 113, 122, 124) | Activity of prodrug to inhibit COX peroxidase activity was not sufficiently studied, as only limited concentrations of prodrug were investigated compared to ketoprofen and other prodrugs |
In vitro study in ARPE19 cells: prodrug uptake Km 8.9 μM, Vmax 62.4 pmol/min/mg protein, Prodrug inhibited 91% of [14C]L-leucine cellular uptake Prodrug uptake was inhibited by LAT1 inhibitor by 88% In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: Prodrug cellular uptake was significantly inhibited by LAT1 inhibitor in neurons, astrocytes, and microglia |
In situ brain perfusion in mice: rate of BBB permeation of prodrug Kin 0.36 µL/s/g In vivo PK study in mice: after a single dose of 25 μmol/kg prodrug i.p.: AUCu,brain/AUCu,plasma 0.008 for prodrug, AUCu,brain/AUCu,plasma 0.13 for released parent drug, while AUCu,brain/AUCu,plasma of ketoprofen 0.01 after parent drug dosing |
In vitro brain slice method in mice: Kp,uu,brain 0.006 for prodrug compared to Kp,uu,brain 0.042 for parent drug, Vu,brain prodrug 24 mL/g brain and Kp,uu,cell of prodrug 1.4 Vu,brain parent drug 1.5 mL/g brain, Kp,uu,cell 0.19 for parent drug In vitro brain slice method in rats: Vu,brain prodrug 31 mL/g brain, Kp,uu,cell 1.9 for prodrug Vu, brain parent drug 1.8 mL/g brain, Kp,uu,cell 0.24 |
In vivo study in LPS-induced inflammation mouse model: no improvement of reduction of prostaglandin E2 levels in the brain after prodrug dosing compared to parent drug dosing |
NR |
| Para-conjugated phenylalanine prodrug of ketoprofen (79) | NR |
In vitro study in ARPE19 cells: prodrug uptake Km 7.6 μM and Vmax 68.4 pmol/min/mg protein, Prodrug inhibited 76% of [14C]L-leucine cellular uptake Prodrug uptake inhibited by LAT1 inhibitor by 65.9% |
In situ brain perfusion in mice: rate of BBB permeation of prodrug Kin 0.31 µL/s/g In vivo PK study in mice: after a single dose of 25 μmol/kg prodrug i.p.: AUCu,brain/AUCu,plasma 0.009 for prodrug, AUCu,brain/AUCu,plasma 0.35 of released parent drug, while AUCu,brain/AUCu,plasma 0.01 of ketoprofen after parent drug dosing |
NR | NR | NR |
| Meta-conjugated phenylalanine prodrug of ketoprofen with additional methylene linker (79) | NR |
In vitro study in ARPE19 cells: prodrug uptake Km 3.8 μM and Vmax 16.7 pmol/min/mg protein Prodrug inhibited 88% of [14C]L-leucine cellular uptake Prodrug uptake inhibited by LAT1 inhibitor by 72% |
In situ brain perfusion in mice: rate of BBB permeation of prodrug Kin 0.29 µL/s/g In vivo PK study in mice: after a single dose of 25 μmol/kg prodrug i.p.: AUCu,brain/AUCu,plasma 0.001 for prodrug, no detected parent drug in the brain |
NR | NR | NR |
| Ketoprofen derivative with aliphatic amino acid promoiety (79, 113) | Active prodrug, as demonstrated by inhibition of COX peroxidase activity in vitro (IC50 2.26 µM) |
In vitro study in ARPE19 cells: prodrug uptake Km 19.8 μM and Vmax 110 pmol/min/mg protein Prodrug inhibited 6.2% of [14C]L-leucine cellular uptake Prodrug uptake inhibited by LAT1 inhibitor by 63% |
In situ brain perfusion in mice: rate of BBB permeation of prodrug Kin 0.45 µL/s/g In vivo PK study in mice: after a single dose of 25 μmol/kg prodrug i.p.: AUCu,brain/AUCu,plasma 0.35 for prodrug, no detected parent drug in the brain after prodrugs’ dosing |
NR | NR | NR |
| Ester-based meta-conjugated phenylalanine derivative of ketoprofen (113, 122, 125) | Active prodrugs, as demonstrated by inhibition of COX peroxidase activity in vitro (IC50 0.58 µM) |
In vitro study in MCF7 cells: prodrug uptake Vmax 0.24 nmol/min/mg protein and Km 49.2 µM Uptake of prodrug was not inhibited by LAT1 inhibitor, but by probenecid sensitive inhibitor In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: prodrug uptake was significantly inhibited by LAT1 inhibitor in neurons, astrocytes, and microglia |
NR |
In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: Concentration-dependent uptake in mouse primary neurons, astrocytes, and microglia at concentration 25, 50, 100 μM |
NR | NR |
| L-lysine apigenin carbamate (126) | NR | NR | In vivo PK study in mice: after i.p. administration of 0.4 mg/g prodrug, parent drug was detected in the brain, while after parent drug dosing 0.23 mg/g no parent drug were not detected | NR | NR | NR |
|
Amide-based meta-conjugated phenylalanine prodrug of ferulic acid with an additional methylene |
NR |
In vitro study in ARPE19 cells: prodrug uptake Km 24 μM, Vmax 4.5 pmol/min/mg protein Prodrug inhibited 86% of [14C]L-leucine cellular uptake Prodrug uptake inhibited by LAT1 inhibitor by 65% In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: prodrug uptake was significantly inhibited by LAT1 inhibitor in neurons, astrocytes, and microglia |
In situ brain perfusion in mice: rate of BBB permeation of prodrugs Kin 2.8 µL/s/g In vivo PK study in mice: after a single dose of 25 μmol/kg prodrug i.p.: Kp,brain prodrug 0.32, no released parent drug in the brain |
In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: Concentration-dependent uptake in mouse primary neurons, astrocytes, and microglia at concentration 25, 50, 100 μM |
NR | NR |
| Amide based meta-conjugated phenylalanine prodrug of ferulic acid (122, 127) | NR |
In vitro study in ARPE19 cells: prodrug uptake Km 16 μM, Vmax 1.8 pmol/min/mg protein Prodrug inhibited 62% of [14C]L-leucine cellular uptake Prodrug uptake inhibited by LAT1 inhibitor by 72% In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: prodrug uptake was significantly inhibited by LAT1 inhibitor only in astrocytes |
In situ brain perfusion in mice: rate of BBB permeation of prodrug Kin 1.91 µL/s/g In vivo PK study in mice: Kp,brain prodrug 1.24 Kp,brain released parent drug 0.02, while Kp,brain parent drug 0.01 after parent drug dosing |
In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: Concentration-dependent uptake in mouse primary neurons, astrocytes, and microglia at concentration 25, 50, 100 μM |
NR | NR |
| Ester-based phenylalanine prodrug of ferulic acid (122, 127) | NR |
In vitro study in ARPE19 cells: Prodrug inhibited 55% of [14C]L-leucine cellular uptake, prodrug uptake was not inhibited by LAT1 inhibitor In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: prodrug was not detected in neurons and microglia at concentration < 10 µM, prodrug uptake was not inhibited by LAT1 inhibitor in astrocytes |
NR |
In vitro study in mouse primary neurons and astrocytes, as well as immortalized microglia: Concentration-dependent uptake in mouse primary neurons, astrocytes, and microglia at concentration 25, 50, 100 μM |
NR | NR |
| Prodrug of dopamine conjugated via a secondary carbamate linker to L-tyrosine (119) | NR |
In vitro study in MCF7 cells: concentration-dependent inhibition of [14C]L-leucine cellular uptake by prodrug 12.5–100 µM No saturation of the uptake at concentrations 3.1–100 µM |
NR | NR | NR | NR |
| Prodrugs of efflux inhibitor probenecid (128, 129) | NR |
In vitro study in MCF7 cells: prodrugs with aromatic promoieties inhibited [14C]L-leucine cellular uptake, while the aliphatic amino acid conjugate did not do The uptake of amide-based meta-conjugated phenylalanine prodrug was inhibited by L-tryptophan |
NR | NR |
In vivo PK study in mice: after co-administration of prodrug and vinblastine i.p. 25 µmol/kg, no improvement of brain delivery extent of efflux transporter substrate vinblastine, as Kp,brain of vinblastine was 0.05, while after co-administration with prodrug Kp,brain of vinblastine was 0.048 |
NR |
| Ester-based prodrugs of flurbiprofen, ibuprofen, naproxen and ketoprofen (130) | NR |
In vitro study in mouse immortalized microglia and primary cortical astrocytes: Prodrugs inhibited [14C]L-leucine cellular uptake in microglia and astrocytes, respectively: IC50 of flurbiprofen prodrug 4.2 and 7.3 µM IC50 of ibuprofen prodrug 5.3 and 23 µM IC50 of naproxen prodrug 10 and 15 µM IC50 of ketoprofen prodrug 15 and 112 µM Reported Km values of prodrugs’ uptake are higher than the measured concentrations |
NR | NR | NR | NR |
| Glucose transporters | ||||||
| L-serinyl β-D-glucoside analogues of [Met5]enkephalin (131) | NA | NR | NR | NR | Analgesia effects in mice after i.p. administration of the compound | NR |
| Glucose-chlorambucil derivative (132) | NR |
Inhibition of the uptake of [14C]D-glucose into human erythrocytes by derivative (IC50 0.065 ± 0.015 mM) Concentration-dependent inhibition of [3H]cytochalasin B binding to erythrocytes |
NR | NR | NR | NR |
| D-glucose ester prodrug of 7-chlorokynurenic acid (133, 134) | Prodrug was not active in vitro, as demonstrated by absence of inhibition of [3H]glycine binding | NR |
Cerebral microdialysis study in rats: 1000-fold higher levels of prodrug and parent drug in cortical perfusate 2 h after i.p. injections of equal dose of prodrug and parent drug 200 mg/kg No plasma concentration reported |
In vitro study in mouse cortical cultures containing both neurons and astrocytes: uptake and bioconversion of prodrug to parent drug |
In vivo study in mice: Protective effect against seizures induced NMDA in mice after i.p. injection of prodrug 200 mg/kg with anticonvulsive activity, while parent drug did not show efficacy |
NR |
| Glycosyl prodrugs of dopamine (135) | Prodrugs were not active as they did not inhibit the binding of [3H]spiperone to D2 receptor |
Inhibition of the uptake of [14C]D-glucose into human erythrocytes by prodrugs (IC50s 12.1—100 mM) |
NR | NR |
In vivo study in reserpinized mice: no antiparkinsonian properties were revealed for the prodrugs |
NR |
| Glycosyl prodrugs of dopamine (136) | NR | Inhibition of the uptake of [14C]D-glucose into human erythrocytes by prodrugs (IC50s 1.5—100 mM) | NR | NR | NR | NR |
| Glycose and galactose derivative of dopamine and L-dopa (137, 138) | NR |
Inhibition of the uptake of [3H]3-O-methylglucose in HRPE by glycosyl dopamine prodrug coupled via a succinic space (IC50 2.6 ± 0.6 mM) The uptake of the prodrug was inhibited by 10 mM D-glucose |
NR | NR |
In vivo study of effect on morphine induced locomotion in mice: glycosyl prodrug of L-dopa was more potent in reducing morphine-induced locomotion than L-dopa or galactose derivative of L-dopa In vivo study in reserpinized rats: glycosyl and galactose derivative of dopamine derivatives showed similar efficacy in reversing hypolocomotion, and were more active than L-dopa or ester glycosyl and galactose prodrugs of L-dopa |
NR |
| Glycosyl prodrug of GW196771 (139) | NR | NR | In vivo PK study in rat: improvement of brain penetration after i.v. injection of 1 mg/kg dose of prodrug compared to parent compound | NR | NR | NR |
| Dopamine-gluconamine (IPX-750) and dopamine-gluconamide (IPX-760) (140) | IPX-750 and IPX-760 bind and activates D1/D5 receptors in vitro | NR | NR | NR |
In vivo study in Parkinson’s disease models, MPTP-lesioned mice and Nurr1(+ / −) knockout mouse and 6-OHDA lesioned rats: Improved locomotor performance after IPX-750 treatment |
NR |
|
Ketoprofen-glucose prodrug, indomethacin-glucose prodrug (141) |
NR |
In situ brain perfusion in rats: inhibition of BBB uptake of 0.2 μCi/mL [14C]D-glucose by ketoprofen and indomethacin prodrugs (IC50s 33.0 ± 8.2 μM 0.71 ± 0.04 µM, respectively) Reduction of the brain uptake of ketoprofen prodrug by 61.4% and no effect on indomethacin prodrug uptake after co-perfusion with 50 mM with D-glucose |
In situ brain perfusion in rats: rate of BBB permeation of 150 μM ketoprofen prodrug 1.3 ± 0.18 pmol/mg/min, rate of BBB permeation of 150 μM indomethacin prodrug 1.9 ± 0.43 pmol/mg/min |
NR | NR | NR |
|
Glycosyl thiamine disulfide prodrugs of naproxen with lock-in function (142) |
NR | NR |
In vivo PK study in mice: more than 1.7-fold higher AUC0-240 min,brain after i.v. injection of 10 mg/kg of prodrugs, Kp,brain of released parent drug ranged 0.36–0.42, while for parent drug itself 0.49 |
NR | NR | NR |
| Naproxen prodrug conjugated to glucose (143) | NR | NR |
In vivo PK study in mice: 2.0 times higher AUC0-480 min,brain and 1.9 times higher Cmax of total released parent drug after i.v. administration of prodrug compared to parent drug itself |
NR |
In vivo study in cerebral ischemia rat model: Increased neuroprotective effect after prodrug administration compared to parent drug itself |
NR |
| Venlafaxine-thiamine disulfide-glucose prodrug (V-TDS-G) and venlafaxine-glucose prodrug (V-G) (144) | NR | NR |
In vivo PK study in mice: after i.v. injection of 10 mg/kg Kp,brain of released parent drug from V-TDS-G was 1.19, Kp,brain of released parent drug from V-G was 0.44, Kp,brain of parent drug after venlafaxine dosing was 0.24 |
NR | NR | NR |
| Ibuprofen prodrug conjugated to glucose (145) | In vitro study: not significant neuroprotective effect in H2O2-induced oxidative stress and injury PC12 cells treated with prodrug | NR |
In vivo PK study in mice: 2.1 times higher AUC0-480 min,brain and 4.1 times higher Cmax of total released parent drug after i.v. administration of 10 mg/kg prodrug compared to parent drug itself Kp,brain of released parent drug 0.51, while for parent drug itself 0.34 |
NR | In vivo cerebral ischemia rat model: greater neuroprotective properties after i.v. administration of prodrug compared to parent drug | NR |
| Ester-based prodrugs of ibuprofen conjugated to D-glucose (146) | NR | NR |
In vivo PK study in rats: After i.v. injection of 18 mg/kg of prodrugs or 10 mg/kg of parent drug, Kp,brain of released parent drug was 0.19—0.57 compared to Kp,brain 0.58 after parent drug dosing |
NR | NR | NR |
| SVCT2 | ||||||
| Naproxen prodrug conjugated to ascorbic acid (143) | NR | NR |
In vivo PK study in mice: 2.1 times higher AUC0-480 min,brain and 2.2 times higher Cmax of total released parent drug after i.v. administration of prodrug compared to parent drug itself |
NR |
In vivo study in cerebral ischemia rat model: Increased neuroprotective effect after prodrug administration compared to parent drug itself |
NR |
| Ibuprofen prodrugs conjugated to ascorbic acid (147) | NR | NR |
In vivo PK study in mice: 4.1 times higher AUC0-240 min,brain and 7.5 times higher Cmax of total released parent drug after i.v. administration of 48 mmol/g prodrug compared to parent drug itself Kp,brain of released parent drug 0.51, while for parent drug itself 0.54 |
NR | NR | NR |
| Ibuprofen prodrug conjugated to ascorbic acid (145) | In vitro study: not significant neuroprotective effect in H2O2-induced oxidative stress and injury PC12 cells treated with prodrug | NR |
In vivo PK study in mice: 2.4 times higher AUC0-480 min,brain and 4.2 times higher Cmax of total released parent drug after i.v. administration of 10 mg/kg prodrug compared to parent drug itself Kp,brain of released parent drug 0.63, while for parent drug itself 0.34 |
NR | In vivo cerebral ischemia rat model: greater neuroprotective properties after i.v. administration of prodrug compared to parent drug | NR |
| Dual targeting to GLUTs and SVCT2 | ||||||
| Dual naproxen prodrug conjugated to glucose and ascorbic acid (143) | NR | NR |
In vivo PK study in mice: 2.4 times higher AUC0-480 min,brain and 2.9 times higher Cmax of total released parent drug after i.v. administration of prodrug compared to parent drug itself |
NR |
In vivo study in cerebral ischemia rat model: Increased neuroprotective effect after prodrug administration compared to parent drug itself |
NR |
| Dual ibuprofen prodrug conjugated to glucose and ascorbic acid (147) | NR | NR |
In vivo PK study in mice: more than 4.1 times higher AUC0-240 min,brain and 7.4 times higher Cmax of total released parent drug after i.v. administration of 48 mmol/g prodrug compared to parent drug itself Kp,brain of released parent drug 0.25 while for parent drug itself 0.54 |
NR | NR | NR |
| Ibuprofen prodrug conjugated to glucose and ascorbic acid (145) | In vitro study: not significant neuroprotective effect in H2O2-induced oxidative stress and injury PC12 cells treated with prodrug | NR |
In vivo PK study in mice: 2.6 times higher AUC0-480 min,brain and 5.2 times higher Cmax of total released parent drug after i.v. administration of 10 mg/kg prodrug compared to parent drug itself Kp,brain of released parent drug – 0.69, while for parent drug itself – 0.34 |
NR | In vivo cerebral ischemia rat model: greater neuroprotective properties after i.v. administration of prodrug compared to parent drug | NR |
| OCTN2 | ||||||
| L-carnitine prodrug of nipecotic acid (148) | NR | NR | In vivo PK study in mice: parent drug was detected in the brain 30 min after i.p. injection of 0.75 mmol/kg of prodrug, while no parent drug was detected after parent drug dosing | NR | In vivo study in mice with PTZ-induced convulsions: increase in latency of tonic convulsions after prodrug i.p. injection 75 mmol/kg, while no effect was observed after parent drug itself | NR |
| Glutathione transporters | ||||||
| Prodrug of adamantamine conjugated to glutathione analogue (149) | NR | Inhibition of the uptake of [3H]glutathione transport across MDCKII cell monolayer by the prodrug | NR | NR | NR | NR |
| Prodrug of dopamine conjugated to glutathione analogue (149) | NR | Inhibition of the uptake of [3H]glutathione transport across MDCKII cell monolayer after the prodrug | NR | NR | NR | NR |
| Glutathione derivative of L-dopa (150) | Antioxidant activities of prodrugs in test involving Fe(II)/H2O2-induced deoxyribose degradation | NR | In vivo PK study in rats: after intragastric administration of 0.332 mmol/kg prodrugs in rats prolonged basal levels of striatal dopamine and L-dopa with lower Cmax than after parent drug dosing | NR | In vivo study in rats: decreased locomotion and impaired grooming behaviour after 0.332 mmol/kg prodrug in rats, which was comparable to that after parent drug dosing | NR |
| Modified glutathione derivative of L-dopa (151) | Antioxidant activity in the DPPH-HPLC and the DMSO competition methods | NR |
In vivo PK study in rats: after intragastric administration of 0.332 mmol/kg prodrug in rats increased basal levels of striatal dopamine and L-dopa |
NR | NR | NR |
ARPE19—Human retinal pigment epithelial cell line; AUC—Area under the drug concentration − time curve; BCH—2-amino-2-Norbornanecarboxylic Acid; DMSO—Dimethyl sulfoxide; DPPH-HPLC—2,2-diphenyl-1-picrylhydrazyl-high performance liquid chromatography; COX-Cyclooxygenase; Cmax—Maximum concentration; IC50—Concentration at which a substance exerts half of its maximal inhibitory effect; MDCKII—Madin Darby canine kidney cell line, MPTP—1,2,3,6-methyl-phenyl-tetrahydropyridin; NA – Not applicable; NR – Not reported; NMDA—N-methyl-D-aspartate,, 6-OHDA—6-hydroxydopamin, PK – Pharmacokinetics; Ki—Inhibitory constant; Kp,brain—Ratio of total brain to total plasma drug concentrations; Kp,uu,brain—Ratio of brain ISF to plasma unbound drug concentrations