Antiviral Drug Delivery System for Enhanced Bioactivity, Better Metabolism and Pharmacokinetic Characteristics

Figures & data

Figure 1 The schematic diagram for antiviral drug delivery systems to improve bioactivity, increase metabolism and pharmacokinetic characteristics. (A) AvDs have poor absorption due to low solubility/low permeability. (B) drug delivery systems are used to enhance absorption and bioavailability of AvDs. (C) AvDs are metabolized by hepatic microsomal enzymes. (D) The pharmacodynamics activities of AvDs are enhanced. The upward arrows (↑↑↑): refers to an increase in the absorption/bioavailability of the drug.

Table 1 Solubility and Permeability of AvDs

Structure	AvD	Antiviral Spectrum	Solubility	Permeability	BCS	Structure	AvD	Antiviral Spectrum	Solubility	Permeability	BCS
			D0	LogP					D0	LogP
Nucleoside Analogs						Non-Nucleoside Analogs
	Ribavirin	Broad-spectrum	0.12	−1.85^Citation19	III	Quinolines	Chloroquine	Broad-spectrum	37.66	4.69	II
	Remdesivir	Broad-spectrum	1.18	2.10	II	Amides	Lopinavir	Anti-CoV	0.21E+06	3.69	II
	Favipiravir	Broad-spectrum	8.21	0.83	IV		Oseltamivir	Anti-influenza	0.44	0.36^Citation20	III
	Zidovudine	Anti-HIV	0.15	0.05	III	Indoles	Arbidol	Broad-spectrum	0.42E+03	4.64	II
	Lamivudine	Anti-HBV, HIV	0.15	−1.40	III	Thiazoles	Ritonavir	Anti-CoV	0.16E+03	3.10^Citation21	II
	Adefovir	Anti-HBV	9.44E-04	−2.06	III	Cyclopen tane	Peramivir	Anti-influenza	2.36	3.12	II
	Entecavir	Anti-HBV	3.03E-04	−0.96^Citation22	III	–	Baloxavir Marboxil	Anti-influenza	1.60	2.24	II
	Aciclovir	Anti-HSV	8.00E-04	−1.56	III	–	Letermovir	Anti-CMV	1.92	3.47	II

Abbreviation: AvD, antiviral drug.

Figure 2 The classification ratio of antiviral drugs (AvDs) according to the biopharmaceutics classification system (BCS) criteria.

Figure 3 Structures of AvDs. Basic structures of (A) adenine nucleotide analog, (B) guanine nucleotide analog, (C) thymine nucleotide analog, (D) cytosine, (E) quinolones, (F) indoles, (G) thiazoles nucleotide analog; (H) baloxavir marboxil; (I) letermovir.

Table 2 Main Metabolic Pathway of AvDs in Liver and Intestine

AvD	Structure	Phase I Reaction			Phase II Reaction	Ref.
		Oxidation	Reduction	Hydrolysis	Binding
Ribavirin		–	Deribosylation at 2: —N—C→—N—H	Amide hydrolysis at 3: —NH2→—COOH	Phosphorylation at 1: —OH→—OPO3→ —O(PO3)2→—O(PO3)3	[^Citation50]
Remdesivir		–	–	–	Phosphorylation at 1: —OH→—OPO3→ —O(PO3)2→—O(PO3)3	[^Citation51]
Favipiravir		–	–	–	Phosphorylation at 1: —OH→—OPO3→ —O(PO3)2→—O(PO3)3 Glucuronidation at 1: —C—F→—C—ADP	[^Citation52]
Zidovudine		–	CYP-450/P450 reduction at 2: —N—N2→—N—H2	–	Phosphorylation at 1: —OH→—OPO3→ —O(PO3)2→—O(PO3)3 Glucuronidation at 1: —OH+;Glucuronic acid →Glucuronides	[^Citation53]
Lamivudine		–	–	–	Phosphorylation at 1: —OH→—OPO3→ —O(PO3)2→—O(PO3)3	[^Citation54]
Adefovir		–	–	–	Phosphorylation at 1: —OPO3→—O(PO3)2→ —O(PO3)3	[^Citation55]
Entecavir		–	–	–	Phosphorylation at 1: —OPO3→—O(PO3)2→ —O(PO3)3	[^Citation56]
Chloroquine		–	Dealkylate at 1,2,3: —N—C→—N—H	–	–	[^Citation57]
Lopinavir		Hydroxylation at 1: —NH→—C—OH→—C—O=O	–	–	–	[^Citation58]
Oseltamivir		Hydroxylation at 2: —C—H→C—OH Carbonylation: —C—H→—C=O	–	Hydrolysis at 1: —O—C→—O—H	–	[^Citation59]
Arbidol		S-Oxidation at 4; Hydroxylation at 5: —C—H→ —C—OH	N-demethylation,di-N-demethylation at 1: —N—C→—N—H; N-demethylation at 3: —N—C→—N—H	–	O-Glucuronide conjugation, O-Sulfate conjugation at 2,5.	[^Citation60]
Ritonavir		Hydroxylation at 2: —C—H→ —C—OH; S-oxide,N-oxide,epoxide at 3,5	Dealkylation at 1,4,6: —N—C→—N—H	–	–	[^Citation61]

Table 3 Pharmacological Activities of AvDs

AvD	Anti-Virus Type	Mechanism	Cell	Parameter				Ref.
				EC50 (μM)	CC50 (μM)	IC50 (μM)	SI
Ribavirin	Anti COVID-19	Prevented viral replication by inhibiting viral DNA polymerase, inhibited viral penetration and viral protein synthesis	Vero E6	105.90	>400.00	–	>3.65	[^Citation12]
	Anti influenza virus	Acted by GTP depletion via inosine monophosphate dehydrogenase (IMPDH) inhibition.	Canine Kidney (MDCK) epithelial	0.34E-02	–	–	–	[^Citation76]
	Anti influenza virus	Acted by GTP depletion via IMPDH inhibition.	MDCK epithelial	0.37E-02	–	–	–	[^Citation76]
	Anti-HCV	Inhibited IMPDH	HuH6	87.00	>135.00	–	>1.55	[^Citation77]
	Anti-RSV	Inhibited virus replication	HEp2	11.00	42.00	–	3.82	[^Citation78]
	Anti Lassa virus	(1) Limited the infectivity of new virions; (2) Reduced viremia by impairing viral production; (3) Modulated cell damage, and (4) Enhanced antiviral immunity.	Vero E6	–	–	26.00	–	[^Citation79]
	Anti CCHF virus	Inhibited virus replication	Vero E6	–	–	2.80µg/mL	–	[^Citation80]
	Anti Chikungunya virus	Reduced viral burden	HUH-7	2.58 µg/mL	11.95 µg/mL	–	4.63	[^Citation81]
Remdesivir	Anti COVID-19	Incorporated into nascent viral RNA chains and results in premature termination	Vero E6	0.77	>100.00	–	>129.87	[^Citation12]
	Anti Ebola virus	Acted as an alternative substrate and RNA-chain terminator	Primary macrophages	0.09	–	–	–	[^Citation51]
	Anti MERS	Reduced viral loads and improves pulmonary function	Calu-3	0.09	>10.00	–	>100.00	[^Citation82]
	Anti SARS	Inhibits virus replication	HAE	0.07	>10.00	–	>142.86	[^Citation83]
Favipiravir	Anti COVID-19	Reduced viral infection	Vero E6	61.88	> 400.00	–	6.46	[^Citation12]
	Anti Lassa virus	Disrupted viral replication	Vero E6	–	–	29.00	–	[^Citation79]
	Anti CCHF virus	Suppressed virus replication	Vero E6	–	–	1.10 µg/mL	–	[^Citation80]
	Anti Chikungunya virus	Reduced viral burden	HUV-7	20.00 μg/mL	>1000.00 μg/mL	–	>50.00	[^Citation81]
Zidovudine	Anti-HIV	Nucleoside reverse transcriptase inhibitor	CEM-GFP	–	>1000.00	0.52	–	[^Citation84]
Lamivudine	Anti-HIV	Inhibited HIV-1 reverse transcriptase via DNA chain termination	MDCK	–	>1000.00	0.04	–	[^Citation84]
	Anti-HBV	Terminated DNA chain	Hep-G2	0.45	>1000.00	–	–	[^Citation85]
Adefovir	Anti-HBV	Prevented viral replication by inhibiting viral DNA polymerase	Hep-G2	0.96	471.10	–	490.73	[^Citation86]
Entecavir	Anti-HBV	Inhibited the replication of HBV virus and exhibit a highly selective inhibitor of HBV DNA polymerase.	Hep-G2	3.75E-03	30.00	–	8000	[^Citation87]
Aciclovir	Anti-HSV-1	Activated by the viral thymidine-kinase (TK), preventing viral genome replication.	WI 38	0.80 μg/mL	> 200.00 μg/mL	–	> 250.00	[^Citation88]
	Anti-HSV-2	Activated by the viral thymidine-kinase (TK), preventing viral genome replication.	WI 38	1.38 μg/mL	> 200.00 μg/mL	–	> 145.00	[^Citation88]
Chloroquine	Anti COVID-19	Function at both entries, and at post-entry stages of the COVID-19 infection, immune-modulating activity.	Vero E6	1.13	> 100.00	–	> 100.00	[^Citation12]
	Anti SARS-CoV	Increased endosomal pH is required for virus/cell fusion as well as interfering with the glycosylation of cellular receptors of SARS-CoV.	Vero	4.10	>128.00	–	>31.00	[^Citation89]
	Anti MERS-CoV	Inhibited the replication of virus	Vero	3.00	58.10	–	19.40	[^Citation90]
	Anti HCoV-229E-GFP	Inhibited the replication of virus	Vero	3.30	>50.00	–	>15.00	[^Citation90]
	Anti Zika virus	(1) Inhibited endosomal disassembly of the internalized virus and reducing the release of viral RNA to the cytoplasm for replication; (2) inhibited ZIKV RNA replication through blocking ZIKV induced autophagy.	Vero	9.82	134.54	–	13.70	[^Citation91]
Lopinavir	Anti MERS-CoV	Inhibited CoV-virus replication	Vero	8.00	24.40	–	3.10	[^Citation90]
	Anti SARS-CoV	Inhibited CoV-virus replication	Vero	17.10	>32.00	–	>2.00	[^Citation90]
	Anti HCoV-229E-GFP	Inhibited CoV-virus reolication	Vero	6.60	37.60	–	5.70	[^Citation90]
Oseltamivir	Anti-H1N1	Prevented viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.	MDCK	90.60	>900.00	–	>9.90	[^Citation92]
	Anti-H3N2	Prevented viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.	MDCK	0.10	>900.00	–	>9000	[^Citation92]
Arbidol	Ant-COVID-19	Against SARS-CoV-2	Vero E6	4.11	31.79	–	7.73	[^Citation75]
	Anti-HSV-2	Viral entry inhibitors	Hep-2	-	-	5.05 µg/mL	6.46	[^Citation93]
	Anti-H1N1	Blocked the fusion between the viral envelope and the endosomal membrane; modulating virus-induced inflammatory cytokines, including	MDCK	4.40	59.39	–	13.40	[^Citation94]
	Anti-H3N2	Blocked the fusion between the viral envelope and the endosomal membrane; modulating virus-induced inflammatory cytokines, including	MDCK	11.80	59.39	–	5.10	[^Citation94]
	Anti-H9N2	Blocked the fusion between the viral envelope and the endosomal membrane; modulating virus-induced inflammatory cytokines, including	MDCK	6.50	59.39	–	9.10	[^Citation94]
	Anti Ebola virus	Inhibited virus entry and replication	HepG2	2.70	24.40	–	9.00	[^Citation95]
	Anti poliovirus type 3	Inhibited virus entry and replication	HepG2	4.10	28.60	–	7.70	[^Citation95]
	Anti-HBV	Inhibited virus entry and replication	HepG2	17.90	>188.00	–	>11.00	[^Citation95]
	Anti arenavirus	Inhibited virus entry and replication	HepG2	5.80	31.00	–	6.20	[^Citation95]
	Anti human herpesvirus 8	Inhibited virus entry and replication	HepG2	1.60	>60.00	–	>37.00	[^Citation95]
Ritonavir	Anti MERS-CoV	HIV-1 protease inhibitor	Calu-3	24.90	>50.00	–	>2.00	[^Citation82]
Peramivir	Anti-H1N1	Neuraminidase inhibitor	MDCK	643.00nM	>E+05nM	0.48nM	>155.52	[^Citation96]
Baloxavir Marboxil	Anti-H1N1	Polymerase acidic protein inhibitor inhibited cap-dependent endonuclease, inhibited viral mRNA synthesis	MDCK	1.2±0.83 nM	–	–	2500	[^Citation97]
Letermovir	Anti-CMV	Inhibited viral replication	HELF	5.0E-03	64.00	–	12,903	[^Citation98]

Abbreviations: Calu-3 cell, cultured human airway epithelial cell; CC₅₀, half-cytotoxic concentration; CCHF, crimean-congo hemorrhagic fever virus; CMV, cytomegalovirus; CoV, coronavirus; COVID-19, coronavirus disease 2019; EC₅₀, half-maximal effective concentration; HBV, hepatitis C virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HELF, human embryonic lung fibroblast cells; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IFN, interferon; MDCK, Madin Darby canine kidney cell; MERS, Middle East respiratory syndrome; RSV, respiratory syncytial virus; SI, selectivity index; Vero E6 cell, monkey kidney cell line; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 4 The antiviral mechanisms of AvDs include reverse transcription inhibition, integration inhibition, maturation interference. NRTIs refer to nucleoside reverse transcriptase. (1)-(6), (9), (10) belong to nucleoside analogues antiviral drugs (NA-AvDs) written in the color

; (7), (8), (11)-(16) belong to non-nucleoside analogues antiviral drugs (NN-AvDs) written in the color

.

Table 4 Main Pharmacokinetic Properties of AvDs via Oral Administration

AvD	Formulation	Dosage (mg/kg)	Subject (Number)	Pharmacokinetics Parameters						Ref.
				AUC (μg·h·mL^−1)	Tmax (h)	Cmax (μg·mL^−1)	t1/2 (h)	MRT (h)	Cl (L/h)
Ribavirin	Solution	30	SD rats (3)	3.04	1.00	0.43	8.10	–	10.20	[^Citation131]
Favipiravir	Suspension	100	Hamsters (53)	8.02E-05	0.29	25.60	0.55E-01	0.34	–	[^Citation132]
Zidovudine	Solution	10	Wistar rats (3)	6.35E+01	1.00	37.67	1.76	–	–	[^Citation133]
	Lactoferrin nanoparticles	10	Wistar rats (3)	2.52E+02	2.00	49.20	3.07	–	–	[^Citation133]
Lamivudine	Solution	10	Wistar rats (4)	1.87±0.39	1.75±0.43	0.46±0.10	2.02±0.83	3.04±0.11	–	[^Citation134]
Adefovir	Suspension	1.30	Swiss albino mice (16)	1.64±0.17	1.00	0.14±0.01ng/g	7.75±0.10	11.68±0.41	–	[^Citation135]
	Nanosuspension	1.30	Swiss albino mice (16)	2.51±0.21	1.00	0.25±0.02ng/g	6.50±0.11	9.75±0.33	–	[^Citation135]
	Solid lipid nanoparticles	1.30	Swiss albino mice (16)	3.75±0.33	4.00	0.18±0.01ng/g	11.43±0.42	17.67±0.62	–	[^Citation135]
Entecavir	Suspension	1.54E-02	Beagle dogs (6)	0.03±0.01	0.24	0.015.4	4.09±1.99	–	–	[^Citation136]
Acyclovir	Suspension	5	Wistar rats (6)	0.58±0.24	0.43±0.09	0.29±0.09	1.55±0.88	2.29±0.62	–	[^Citation137]
	Semisolid self-microemulsifying	5	Wistar rats (6)	0.92±0.26	0.23±0.18	0.92±0.21	0.73±0.20	1.46±0.53	–	[^Citation137]
Lopinavir	Suspension	20	Wistar rats (5)	1.65±0.05	0.85	0.65± 0.09	–	5.09±0.25	–	[^Citation138]
	Pullulan acetate nanoparticles	20	Wistar rats (5)	8.40±0.10	1.40	1.69±0.16	–	8.57±0.52	–	[^Citation138]
	Suspension	10	Wistar rats (5)	1.60±0.22	0.14±0.02	–	8.45	–	–	[^Citation139]
	PLGA nanoparticles	10	Wistar rats (5)	22.34±2.31	0.83±0.09	–	17.93	–	–	[^Citation139]
	Suspension	52	SD rats (3)	5.04±0.18	6.00±0.00	0.52±0.05	5.81±1.28	6.30± 0.10	–	[^Citation140]
	Kaletra (marketed liquid formulation)	52	SD rats (3)	15.86±0.68	3.00±0.00	1.77 ± 0.20	6.53± 1.45	6.70± 0.31	–	[^Citation140]
	Zein-Whey protein isolate nanoparticles	52	SD rats (3)	23.63±2.21	6.00±0.00	1.29 ± 0.05	11.72±3.30	16.97±3.51	–	[^Citation140]
	Powder	10	SD rats (6)	0.75±0.12	2.00±0.63	0.16±0.02	–	–	–	[^Citation27]
	Extrudate (LPV-VA64-SBM-CLSF =1:4:0.4:0.6, w/w)	10	SD rats (6)	1.34±0.35	1.50±0.55	0.35±0.08	–	–	–	[^Citation27]
	Extrudate (LPV-Soluplus-SBM-CLSF=1:4:0.4:0.6, w/w)	10	SD rats (6)	2.79±0.44	1.83±0.41	0.57±0.10	–	–	–	[^Citation27]
Oseltamivir	Solution (solvent:100 mg/mL distilled water)	10	BALA/c mice (5)	9.80±3.00	0.80±0.30	4.10±1.20	3.80±0.80	–	–	[^Citation92]
	Phosphate solution (solvent:100 mg/mL distilled water)	10	BALA/c mice (5)	9.40±5.10	0.80±0.30	3.30±1.30	2.80±0.70	–	–	[^Citation92]
Arbidol	Suspension	1.30	Swiss albino mice (16)	0.81±0.02	1.00	0.14±0.01	7.75±0.10	11.68±0.41		[^Citation135]
	Nanosuspension	1.30	Swiss albino mice (16)	1.66±0.33	1.00	0.25±0.02	6.50±0.11	9.75±0.33		[^Citation135]
	Solid lipid nanoparticles	1.30	Swiss albino mice (16)	2.77±0.20	4.00	0.18±0.01	11.43±0.42	17.67±0.62		[^Citation135]
	Arbidol hydrochloride monohydrate powders	60	SD rats (6)	1.37±0.11	0.25±0.04	1.30±0.24	2.97±0.46	–	–	[^Citation22]
	Arbidol mesylate powders	65	SD rats (6)	2.73±0.09	0.25±0.03	1.46± 0.17	4.04±0.88	–	–	[^Citation22]
Ritonavir	Powder	10	Wistar rats (6)	0.23±0.10	0.88±0.31	0.09±0.04	4.71±2.69	–	–	[^Citation35]
	Physical mixture	10	Wistar rats (6)	0.35±0.11	0.92±0.20	0.09±0.03	7.91±9.20	–	–	[^Citation35]
	Lyophilized nanosuspension	10	Wistar rats (6)	0.80±0.27	1.17±0.41	0.15±0.04	5.87±1.71	–	–	[^Citation35]
Peramivir	Solution	10	SD rats (6)	1.73±0.21	1.50±0.30	0.38±0.13	5.60±0.60	–	–	[^Citation141]
Baloxavir Marboxil	Tablet	1.00	Adults patients (446)	6.48E-03	–	9.82E-05	–	–	–	[^Citation142]
Letermovir	Solution	120	Healthy volunteer (8)	11.41	1.50	2.61	16.21	–	11.25	[^Citation143]

Abbreviations: p.o, oral administration; SD, to sprague-dawley rat.

Table 5 Main Pharmacokinetic Properties of AvDs via Intravenous Administration

AvD	Formulation	Administration	Dosage (mg/kg)	Subject (Number)	Pharmacokinetics Parameters						Ref.
					AUC (μg·h·mL^−1)	Tmax (h)	Cmax (μg/mL)	t1/2 (h)	MRT (h)	Cl (L/h/kg)
Ribavirin	Injection	i.v.	30.00	SD rats (3)	11.20	–	20.50	9.90	–	2.60	[^Citation131]
Zidovudine	Sterile saline solution	i.v.	8.46	SD rats (3)	5.14±0.48	–	–	1.3±0.09	0.35±0.02	0.47±0.04	[^Citation153]
	Solution of dextrin-AZT conjugate	i.v.	8.46	SD rats (3)	6.09±0.09	–	–	19.34±4.93	23.63±3.04	0.39±0.01	[^Citation153]
	Cholesteryl-ε-polylysine nanogels	i.v.	0.25	Balb/c mice (3)	212.98±1.60	–	–	115.00± 0.18	–	1.92±0.14	[^Citation154]
	Suspension	i.v.	10~15	SD rats (3)	2.00±0.02	–	–	1.15±0.04	1.26±0.08	2.99±0.04	[^Citation155]
	Lipid-based nanocarrier (fatty acid combination)	i.v.	10~15	SD rats (3)	5.41±0.15	–	–	9.71±0.21	6.43±0.28	1.10±0.03	[^Citation155]
	Lipid-based nanocarrier (soya lecithin combination)	i.v.	10~15	SD rats (3)	5.11±0.15	–	–	7.64±0.08	4.09±0.24	1.17±0.03	[^Citation155]
Lamivudine	Solution	i.v.	10.00	SD rats (6)	1.24±0.19	–	7.02±2.37	0.46±0.04	0.38±0.07	8.21±1.29	[^Citation156]
Adefovir	Sulotion (solvent: PEG 400)	i.m.	60.00	Albino rats (6)	667.55 ± 10.54	1.00	7.45±1.98	62.16± 3.52	96.55±4.36	–	[^Citation157]
	PLGA microspheres	i.m.	60.00	Albino rats (6)	81,915.36±207.36	12.00	7.40±1.88	8.62E+03	1.21E+04	–	[^Citation157]
Entecavir	Suspension	s.c.	0.43	Beagle dogs (6)	1.19±0.28	216.00	0.005 ± 0.002	129.30± 46.60	–	–	[^Citation136]
	Suspension	i.m.	2.59	Beagle dogs (3)	4.32±1.27	96.00	0.02±0.01	75.90± 38.40	–	–	[^Citation136]
	PLGA microspheres	i.m.	0.25	SD rats (6)	1.74E+04	96.00	0.03±0.003	28.38± 8.66	562.56 ±99.84	–	[^Citation158]
Acyclovir	Solution (solvent: water)	i.v.	5.00	Wistar rats (6)	15.47±3.65	0.33±0.05	–	0.75±0.21	0.70±0.26	0.34±0.06	[^Citation137]
Lopinavir	Suspension	i.v.	25.00	Macaques (10)	150.00	0.80	48.00	16.00	4.90	–	[^Citation159]
Oseltamivir	Solution (solvent: 100mg/mL distilled water)	i.v.	5	BALA/c mice (5)	14.70± 4.20	–	–	3.20± 0.50	–	–	[^Citation92]
	Phosphate solution (solvent:100 mg/mL distilled water)	i.v.	5	BALA/c mice (5)	10.00±3.30	–	–	1.90± 1.30	–	–	[^Citation92]
Arbidol	Suspension	i.v.	1.30	Swiss albino mice (16)	4.79±0.10	–	–	2.50±0.25	0.01± 0.00	–	[^Citation135]
Ritonavir	Suspension	i.v.	7.20	Macaques (10)	18.00	0.80	16.00	14.00	1.90	–	[^Citation159]
Peramivir	Solution	i.v.	1	SD rats (6)	3.91±0.35	–	–	5.70±0.50	–	–	[^Citation141]

Abbreviations: i.m., intramuscular injection; i.v., intravenous injection; PEG, polyethylene glycol; PLGA, poly-d,l-lactic-co-glycolic acid; s.c, subcutaneous injection.

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