In primary duck hepatocyte (PDH) cultures produced from ducklings congenitally infected with the duck hepatitis B virus (DHBV), lamivudine (1 μM) exhibits antiviral activity and is a powerful inhibitor of hepatitis B virus (HBV) replication[1]. Inhibiting DHBV replication, lamivudine (0–20 μM; 2, 4, 9 d) has a 50% inhibitory dose of 0.55 μM[1]. When lamivudine and penciclovir (9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine [PCV]) are coupled (1 μM; 2, 4, 9 d), they exhibit a synergistic impact that is particularly effective in decreasing the typically resistant viral covalently closed circular (CCC) DNA type of DHBV[1].

Lamivudine is toxic to rat liver and produces oxidative stress (20–500 mg/kg/d; po; 15 or 45 d)[2]. In rat brain regions susceptible to HIV neurodegeneration, lamivudine (50 mg/kg; ip; single dose) localizes and penetrates the central nervous system (CNS) effectively[3]. In HIV-positive rats, the pharmacokinetic parameters of lamivudine were as follows: Cmax (μg/mL) Parameter Tmax (h) T1/2 (h) AUC (h·ng/mL) Plasma 25,846 0.25 0.68 22,172 Brain 272 0.5 1.2 967 The 24-hour period was used to collect the pharmacokinetic data, with sampling occurring at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, and 24.0 hours after medication.

Animal/Disease Models: Wistar female rats[2]
Doses: 20-500 mg/kg/day
Route of Administration: po (oral gavage); single or repeated dose; 15 or 45 days
Experimental Results: Increased activities of the aminotransferases (ALT and AST), γ-glutamyltransferase (GGT) and total protein concentration in serum at 500 mg/kg dose. Increased activities of glutathione S-transferase (GST), GGT and superoxide dismutase (SOD) as well as concentrations of malondialdehyde (MDA) and protein at 20 mg/kg dose. Caused multifocal lymphocyte population and hepatocyte edema degeneration in hepatic sinusoids of chickens.

Absorption, Distribution and Excretion
Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.
The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Lamivudine is excreted in human breast milk and into the milk of lactating rats.
Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.
Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects]
Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients]
Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]
Lamivudine crosses the placenta and has been detected in the fetal circulation.
Lamivudine has high oral bioavailability with or without food and reaches peak plasma levels within approximately 1 hour.

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Metabolism / Metabolites
Metabolism of lamivudine is a minor route of elimination. In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. This biotransformation is catalyzed by sulfotransferases.

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Biological Half-Life
5 to 7 hours (healthy or HBV-infected patients)

Hepatotoxicity
Elevations in serum ALT levels occur in a proportion of patients with chronic hepatitis B treated with lamivudine. These elevations appear to be due to a transient flare in the underlying chronic hepatitis B and occur in three situations during and after therapy: upon initiation of therapy (treatment flares), upon development of antiviral resistance (breakthrough flares), and shortly after stopping therapy (withdrawal flares). Treatment flares typically occur during the first few months of therapy and are marked by asymptomatic elevations in serum aminotransferase levels and rarely with jaundice or symptoms (Case 1). These flares occur during the rapid decrease in HBV DNA levels with initiation of therapy. An exacerbation of hepatitis also typically occurs after development of lamivudine resistance, a few weeks or months after the initial appearance of the mutant HBV strain and rise in HBV DNA levels (Case 2). Finally, withdrawal flares occur between 4 and 12 weeks after stopping lamivudine and can be severe, symptomatic and even lead to clinical decompensation, acute liver failure and either death or need for emergency liver transplantation. Resistance and withdrawal flares typically occur as HBV DNA levels are high or rising.
Other forms of hepatotoxicity from lamivudine are extremely rare if they occur at all. Lamivudine is a rare cause of liver test abnormalities or clinically apparent liver injury in patients with HIV infection without hepatitis B. Although several instances of lactic acidosis with hepatic steatosis and liver failure have been reported in patients receiving lamivudine, in all instances other nucleoside analogues more clearly associated with mitochondrial injury [didanosine, stavudine, zalcitrabine, zidovudine] were also being taken. No convincing instances of lactic acidosis with microvesicular fat have been reported in patients with hepatitis B who typically receive lamivudine alone or in combination with adefovir or tenofovir.
Likelihood score: E (unlikely cause of clinically apparent liver injury although flares of hepatitis B can occur during or following therapy).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Lamivudine has been well studied in HIV-positive nursing mothers and appears to be well tolerated by their breastfed infants. It has not been studied in HIV-negative nursing mothers being treated for hepatitis B infection, but the low doses used would not be expected to cause any serious adverse effects in breastfed infants. The manufacturer estimates that a breastfed infant's dose would be about 6% of the infant dose for children over 2 years of age. Achieving and maintaining viral suppression with antiretroviral therapy decreases breastfeeding transmission risk to less than 1%, but not zero. Individuals with HIV who are on antiretroviral therapy with a sustained undetectable viral load and who choose to breastfeed should be supported in this decision. If a viral load is not suppressed, banked pasteurized donor milk or formula is recommended.
An expert review of available data concluded that there is currently no justification for contraindicating the use of lamivudine for hepatitis B therapy during breastfeeding. Some professional organization guidelines allow breastfeeding during lamivudine therapy, although one guideline cautions against it because of a lack of long-term safety data. The lack of long-term safety data with long-term, low-level infant exposure should be discussed with the mother. No differences exist in infection rates between breastfed and formula-fed infants born to hepatitis B-infected women, as long as the infant receives hepatitis B immune globulin and hepatitis B vaccine at birth. Mothers with hepatitis B are encouraged to breastfeed their infants after their infants receive these preventative measures.
◉ Effects in Breastfed Infants
A study assigned pregnant women to zidovudine alone or highly active antiretroviral therapy (HAART: zidovudine, lamivudine and nevirapine) to prevent maternal-to-child transmission of HIV infection. After delivery, all infants received one month of zidovudine prophylaxis; some infants were breastfed and others were formula fed. A higher percentage of infants in the HAART-exposed group had neutropenia than those in the unexposed group at 1 month of age (15.9% and 3.7%, respectively). Hematologic toxicity was transient and asymptomatic. From 2 to 6 months postpartum, no differences in hematologic toxicity were seen between breastfed and formula-fed infants. No statistical difference in hepatic toxicity was seen between the breastfed and formula-fed infants.
Twenty-four infants who were breastfed by HIV-positive mothers developed HIV infection by 6 months of age. Six of these infants had a mutation that might have been selected for by subtherapeutic levels of lamivudine in breastmilk.
An HIV-positive mother took a combination tablet containing dolutegravir 50 mg, abacavir sulfate 600 mg and lamivudine 300 mg (Triumeq) once daily. Her infant was exclusively breastfed for about 30 weeks and partially breastfed for about 20 weeks more. No obvious side effects were noted.
One mother took lamivudine for 33 days, 25 before birth and eight days postpartum for chronic hepatitis B infection. Her infant was breastfed (extent not stated). At three months of age, the infant died with the death attributed to sudden infant death syndrome. The death was unlikely to be related to lamivudine.
◉ Effects on Lactation and Breastmilk
Gynecomastia has been reported among men receiving highly active antiretroviral therapy. Gynecomastia is unilateral initially, but progresses to bilateral in about half of cases. No alterations in serum prolactin were noted and spontaneous resolution usually occurred within one year, even with continuation of the regimen. Some case reports and in vitro studies have suggested that protease inhibitors might cause hyperprolactinemia and galactorrhea in some male patients, although this has been disputed. The relevance of these findings to nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
<36% bound to plasma protein.

[1]. Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penciclovir in vitro. Hepatology. 1997 Jul;26(1):216-25.

[2]. Lamivudine-Induced Liver Injury. Open Access Maced J Med Sci. 2015 Dec 15;3(4):545-50.

[3]. Zidovudine and Lamivudine as Potential Agents to Combat HIV-Associated Neurocognitive Disorder. Assay Drug Dev Technol. 2019 Oct;17(7):322-329.

Lamivudine is a monothioacetal that consists of cytosine having a (2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl moiety attached at position 1. An inhibitor of HIV-1 reverse transcriptase, it is used as an antiviral in the treatment of AIDS and hepatitis B. It has a role as a HIV-1 reverse transcriptase inhibitor, an antiviral drug, an anti-HBV agent, an allergen, a prodrug and an EC 2.7.7.49 (RNA-directed DNA polymerase) inhibitor. It is a monothioacetal, a primary alcohol, an oxacycle and a nucleoside analogue. It is functionally related to a cytosine.
Lamivudine (brand name: Epivir) is a prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV infection in adults and children. Lamivudine is always used in combination with other HIV medicines.
A reverse transcriptase inhibitor and zalcitabine analog in which a sulfur atom replaces the 3' carbon of the pentose ring. It is used to treat Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV).
Lamivudine is a Hepatitis B Virus Nucleoside Analog Reverse Transcriptase Inhibitor and Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor. The mechanism of action of lamivudine is as a Nucleoside Reverse Transcriptase Inhibitor.
Lamivudine is a nucleoside analogue and reverse transcriptase inhibitor used in the therapy of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Lamivudine is a very rare cause of clinically apparent drug induced liver injury, but is associated with flares of underlying hepatitis B during therapy or with abrupt withdrawal.
Lamivudine has been reported in Schisandra bicolor and Vitex tripinnata with data available.
Lamivudine is a synthetic nucleoside analogue with activity against hepatitis B virus (HBV) and HIV. Intracellularly, lamivudine is phosphorylated to its active metabolites, lamiduvine triphosphate (L-TP) and lamiduvine monophosphate (L-MP). In HIV, L-TP inhibits HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleoside analogue into viral DNA. In HBV, incorporation of L-MP into viral DNA by HBV polymerase results in DNA chain termination. L-TP is a weak inhibitor of mammalian DNA polymerases alpha and beta, and mitochondrial DNA polymerase. (NCI04)
A reverse transcriptase inhibitor and ZALCITABINE analog in which a sulfur atom replaces the 3' carbon of the pentose ring. It is used to treat HIV disease.

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Drug Indication
For the treatment of HIV infection and chronic hepatitis B (HBV).
FDA Label
Lamivudine Teva Pharma B. V. is indicated as part of antiretroviral combination therapy for the treatment of human-immunodeficiency-virus (HIV)-infected adults and children.
Lamivudine Teva is indicated for the treatment of chronic hepatitis B in adults with: compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and / or fibrosis. Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier is not available or appropriate (see in section 5. 1).
Epivir is indicated as part of antiretroviral combination therapy for the treatment of human-immunodeficiency-virus (HIV)-infected adults and children. ,
Zeffix is indicated for the treatment of chronic hepatitis B in adults with: , , , compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active liver inflammation and / or fibrosis. Initiation of lamivudine treatment should only be considered when the use of an alternative antiviral agent with a higher genetic barrier is not available or appropriate; , decompensated liver disease in combination with a second agent without cross-resistance to lamivudine. , ,

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Mechanism of Action
Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.
Lamivudine enters cells by passive diffusion and is phosphorylated to its active metabolite, lamivudine triphosphate. Lamivudine triphosphate competes with deoxycytidine triphosphate for binding to reverse transcriptase, and incorporation into DNA results in chain termination. Lamivudine has very low affinity for human alpha and omega DNA polymerases, moderate affinity for beta DNA polymerase, and higher affinity for gamma DNA polymerase.

C8H11N3O3S

229.26

229.052

134678-17-4

Lamivudine salicylate;173522-96-8

60825

White to off-white solid powder

1.7±0.1 g/cm3

475.4±55.0 °C at 760 mmHg

177 °C

241.3±31.5 °C

0.0±2.7 mmHg at 25°C

1.755

-0.71

2

4

2

15

331

2

C1[C@H](O[C@H](S1)CO)N2C=CC(=NC2=O)N

JTEGQNOMFQHVDC-NKWVEPMBSA-N

InChI=1S/C8H11N3O3S/c9-5-1-2-11(8(13)10-5)6-4-15-7(3-12)14-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7+/m0/s1

4-amino-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (10.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (10.90 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (10.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 100 mg/mL (436.19 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)