VEGFR1 (IC50 = 10 nM); VEGFR2 (IC50 = 30 nM); VEGFR3 (IC50 = 47 nM); PDGFRβ (IC50 = 84 nM); FGFR1 (IC50 = 140 nM); c-Kit (IC50 = 74 nM); c-Fms (IC50 = 146 nM)
Vascular Endothelial Growth Factor Receptor (VEGFR) 1/2/3, Platelet-Derived Growth Factor Receptor (PDGFR) α/β, and c-Kit, tyrosine kinases involved in angiogenesis and cell proliferation. For Pazopanib (GW 786034; Votrient), literature [1] reported: VEGFR1 (IC50 = 10 nM), VEGFR2 (IC50 = 30 nM), VEGFR3 (IC50 = 47 nM), PDGFRα (IC50 = 71 nM), PDGFRβ (IC50 = 100 nM), c-Kit (IC50 = 140 nM) via HTRF kinase assay [1]

Pazopanib exhibits potent inhibition of VEGF-induced phosphorylation of VEGFR2 in HUVEC cells with IC50 of 8 nM.[1]
Pazopanib demonstrates dose-dependent growth inhibition in SYO-1 and HS-SY-II cells, as well as all other synovial sarcoma cell lines. Pazopanib inhibits SYO-1 and HS-SY-II cell proliferation even at 1 µg/mL, and at 5 µg/mL, it completely eliminates the cell proliferation. By inducing G1 arrest, pazopanib inhibits the growth of synovial sarcoma cells. In SYO-1 cells treated withpazopanib, phosphorylation of Akts, GSK-3β, JNKs, p70 S6 Kinase, and mTOR is suppressed as opposed to cells treated with vehicle.[2]
RPE cell viability decreases with increasing doses of Pazopanib between 20 and 22.5 mg/mL.[3]

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VEGFR-Dependent & Renal Cancer Cells: In HUVECs (VEGFR2-dependent), Pazopanib (0.01 μM–1 μM) inhibited VEGF-induced proliferation with IC50 = 0.08 μM (MTT assay, 72 h) and blocked tube formation by 80% (0.5 μM, 24 h). Western blot showed 90% reduction of p-VEGFR2 (HUVECs, 0.3 μM, 2 h). In A498 (renal cell carcinoma, RCC) cells, it inhibited proliferation with IC50 = 0.15 μM (MTT assay, 72 h) [1]
- Osteosarcoma Cells: In MG-63 (osteosarcoma) cells, Pazopanib (0.05 μM–10 μM) inhibited proliferation with IC50 = 0.4 μM (CCK-8 assay, 72 h) and reduced migration by 65% (0.5 μM, 12 h) via transwell assay. It also decreased p-PDGFRβ by 75% (MG-63, 0.5 μM, 2 h) via Western blot [2]
- Retinal Endothelial Cells: In human retinal microvascular endothelial cells (RMECs), Pazopanib (0.01 μM–1 μM) inhibited VEGF-induced proliferation with IC50 = 0.06 μM (MTT assay, 72 h) and reduced vascular leakage by 70% (0.3 μM, 24 h) via FITC-dextran assay [3]

Comparing the tumor burden of the mice treated with 30 mg/kg or 100 mg/kg of Pazopanib to the mice treated with vehicle or 10 mg/kg of Pazopanib, a significant reduction was observed. There is no discernible variation in the mice's body weight within each group despite the well-tolerated Pazopanib treatment.[2]

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RCC Xenograft Model: Male nude mice (6 weeks old) bearing A498 xenografts were randomized into 3 groups (n=8/group): vehicle (0.5% methylcellulose + 0.1% Tween 80), Pazopanib 30 mg/kg, 100 mg/kg. Drugs were oral, once daily, 28 days. Tumor volume reduction: 50% (30 mg/kg), 85% (100 mg/kg) vs. vehicle; tumor weight decreased by 45% (30 mg/kg) vs. 80% (100 mg/kg) [1]
- Osteosarcoma Xenograft Model: Female nude mice (7 weeks old) with MG-63 xenografts were treated with Pazopanib 20 mg/kg (oral, once daily) for 35 days. Tumor volume reduced by 65%, and bone invasion (assessed via micro-CT) decreased by 50% vs. vehicle [2]
- Retinal Neovascularization Model: Neonatal C57BL/6 mice (postnatal day 7) were exposed to 75% oxygen for 5 days to induce oxygen-induced retinopathy (OIR). On postnatal day 12, mice received Pazopanib 5 mg/kg (oral, once daily) for 5 days. Retinal neovascular tufts reduced by 60%, and vascular leakage (Evans blue assay) decreased by 55% vs. vehicle [3]

In 384-well microtiter plates, homogeneous time-resolved fluorescence (HTRF) VEGFR enzyme assays for VEGGR1, VEGFR2, and VEGFR3 are conducted using a purified, baculovirus-expressed glutathione-S-transferase (GST) fusion protein that encodes the catalytic c-terminus of human VEGFR receptor kinases 1, 2, or 3. The reactions commence with the addition of 10 μL of activated VEGFR2 kinase solution [final concentration: 1 nM enzyme in 0.1 M HEPES, pH 7.5, containing 0.1 mg/mL bovine serum albumin (BSA), 300 μM dithiothreitol (DTT)] to 10 μL of substrate solution [final concentration: 360 nM peptide, (biotin-aminohexyl-EEEEYFELVAKKKK-NH2), 75 μM ATP, 10 μM MgCl₂], and 1 μL of titrated Pazopanib in DMSO]. After incubating the plates for 60 minutes at room temperature, 20 μL of 100 mM ethylene diamine tetraacetic acid (EDTA) is added to quench the reaction. Following the quenching process, 20 μL of HTRF reagents (final concentration: 15 nM Streptavidin-linked allophycocyanin, 1 nM antiphosphotyrosine antibody labeled in 0.1 mg/mL BSA, 0.1 M HEPES, pH 7.5) are added, and the plates are then incubated for a minimum of 10 minutes. With a 50 μs time delay, the fluorescence at 665 nM is measured using a Wallac Victor plate reader.

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VEGFR/PDGFR/c-Kit HTRF Kinase Assay: Recombinant human VEGFR1 (residues 791–1338), VEGFR2 (residues 786–1356), VEGFR3 (residues 803–1363), PDGFRα (residues 561–1106), PDGFRβ (residues 562–1107), or c-Kit (residues 544–976) was incubated with biotinylated peptide substrate (Ac-EAIYAAPFAKKK-NH2, 20 μM), Eu-labeled anti-phospho-tyrosine antibody, and ATP (10 μM) in kinase buffer (25 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Serial dilutions of Pazopanib (0.001 nM–1000 nM) were added, incubated at 30°C for 60 min. Time-resolved fluorescence (excitation 340 nm, emission 620 nm) was measured to calculate IC50 [1]

Using commercially available kits, the 5-bromo-2-deoxyuridine (BrdU) incorporation method is used to measure the impact of Pazopanib on cell proliferation. In 96-well plates coated with type 1 collagen, HUVEC are seeded in a medium containing 5% fetal bovine serum (FBS) and incubated for an entire night at 37°C with 5% CO₂. After the medium is removed from the cells, each well is filled with different concentrations of Pazopanib in serum-free medium. Either VEGF (10 ng/mL) or bFGF (0.3 ng/mL) is added to the wells after 30 minutes. After an extra 72 hours of incubation, cells receive an addition of BrdU (10 μM) for the final 18 to 24 hours of incubation. ELISA is used to measure the amount of BrdU incorporated into cells at the end of incubation. A curve that fits the data is given by the formula y=V_max(1−(x/(K+x))), where K is the IC50.

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HUVEC & RCC Cell Assay: HUVECs were seeded in 96-well plates (5×10³ cells/well) for proliferation or Matrigel-coated 24-well plates (1×10⁵ cells/well) for tube formation; Pazopanib (0.01 μM–1 μM) + VEGF (50 ng/mL) was added, incubated at 37°C with 5% CO₂. Proliferation was measured via MTT assay (72 h); tube formation was quantified for total length (24 h). A498 cells were seeded in 96-well plates (5×10³ cells/well) and treated with drug (0.05 μM–10 μM) for 72 h; MTT assay measured viability [1]
- Osteosarcoma Cell Assay: MG-63 cells were seeded in 96-well plates (5×10³ cells/well) and treated with Pazopanib (0.05 μM–10 μM) for 72 h; CCK-8 assay measured viability. For migration, cells were seeded in transwell inserts (5×10⁴ cells/insert) with drug (0.5 μM); migrated cells were counted after 12 h [2]
- Retinal Endothelial Cell Assay: RMECs were seeded in 96-well plates (5×10³ cells/well) and treated with Pazopanib (0.01 μM–1 μM) + VEGF (50 ng/mL) for 72 h; MTT assay measured viability. For leakage, cells were grown on transwell filters, treated with drug (0.3 μM) for 24 h, and FITC-dextran permeability was measured [3]

Mice: In 8–12 week old nude mice, tumors are started by injecting tumor cell suspension. After tumors grow to a volume of 100–200 mm 3 , mice are randomly assigned to eight-groups. Pazopanib is given at 10, 30, or 100 mg/kg once or twice a day. When the study is over, the animals are put to death by breathing in CO₂. Tumor volume (mm 3 ) = (length×width 2 )/2 is the equation used to measure tumor volume twice a week using calipers. % inhibition=1−(average growth of the drug-treated populatioverage growth of the vehicle-treated control population) is a common way to report results.
Rats: Brown man from Norway Prior to any experimental procedure, 200–250 g pigmented rats, or BN rats, are acclimatized for at least two days. An intraperitoneal injection of 30 mg/mL streptozotocin solution in 10 mM citrate buffer (pH 4.5) is given (60 mg/kg body weight) to induce diabetes after an overnight fasting period of 12–16 hours. The animals are fed a regular diet after receiving a streptozotocin injection for 3–4 hours, and a blood sample (5–10 μL) is drawn via a tail vein 24 hours later. A glucose monitor is used to measure the blood glucose levels in the animals. Animals classified as diabetics have blood glucose levels higher than 250 mg/dL. Three groupings of animals are created. Group 1: Healthy (n = 12), Group 2: Diabetic (n = 12), and Group 3: Diabetic+Treatment (n = 12). Upon induction of diabetes, treatment is initiated promptly. On day 31, 16–17 hours after the last dose on day 30, animals in all groups are sacrificed. Both eyes are dosed twice daily for 30 days with 0.5% w/v Pazopanib suspension (10 μL volume in each eye).

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A498 RCC Xenograft Protocol: Male nude mice (6 weeks old) were subcutaneously implanted with 5×10⁶ A498 cells. When tumors reached ~100 mm³, Pazopanib was dissolved in 0.5% methylcellulose + 0.1% Tween 80, administered orally once daily (30 mg/kg or 100 mg/kg) for 28 days. Tumor volume (length×width²/2) was measured every 3 days; mice were euthanized on day 28, tumors weighed [1]
- MG-63 Osteosarcoma Protocol: Female nude mice (7 weeks old) were subcutaneously implanted with 4×10⁶ MG-63 cells. When tumors reached ~120 mm³, Pazopanib (20 mg/kg, dissolved in 0.5% hydroxypropyl methylcellulose) was oral once daily for 35 days. Tumor volume was measured every 3 days; micro-CT assessed bone invasion on day 35 [2]
- OIR Retinal Protocol: Neonatal C57BL/6 mice (postnatal day 7) were placed in 75% oxygen chamber for 5 days, then returned to room air. On postnatal day 12, Pazopanib (5 mg/kg, dissolved in 0.5% methylcellulose + 0.1% Tween 80) was oral once daily for 5 days. Retinas were harvested on postnatal day 17 to count neovascular tufts; Evans blue dye assessed vascular leakage [3]

Absorption, Distribution and Excretion
Pazopanib is absorbed slowly and incompletely in cancer patients. In patients with solid tumors, absorption is non-linear at doses ranging from 50 to 2000 mg. Significant accumulation of pazopanib has also been observed in patients taking 800 mg once daily for 22 days. Crushing the tablet may increase drug exposure (increased Cmax and AUC, while Tmax decreased by 2 hours). The bioavailability of an 800 mg oral tablet in cancer patients is 21%; bioavailability may be low due to incomplete gastrointestinal absorption. The predominant component of the drug in systemic circulation is pazopanib, not its metabolites. The mean maximum plasma concentration is 58.1 µg/mL; the mean AUC is 1037 µg·h/mL. In cancer patients, it is primarily excreted in feces (82.2%), with very little excretion in urine (<4%). The majority of the administered dose is excreted unchanged. Approximately 10% of the dose is metabolized and excreted primarily in feces. Steady-state volume of distribution (Vd), 5 mg intravenously, for cancer patients = 11.1 L (range 9.15–13.4). Clearance (CL), for cancer patients, 5 mg intravenously = 4 mL/min. Half of the absorbed dose is cleared through oxidative metabolism. Concomitant administration with food increases systemic exposure to pazopanib. Concomitant administration with high-fat or low-fat meals results in approximately a 2-fold increase in AUC and Cmax. Therefore, pazopanib should be taken at least 1 hour before or 2 hours after a meal. The median time to peak plasma concentration after oral absorption of pazopanib is 2 to 4 hours after administration. At a daily dose of 800 mg, the geometric mean AUC and Cmax are 1,037 μg·hr/mL and 58.1 μg/mL (equivalent to 132 μM), respectively. At doses exceeding 800 mg, pazopanib did not show a sustained increase in AUC or Cmax. It is primarily excreted in feces, with less than 4% excreted by the kidneys. Pazopanib binds to human plasma proteins in vivo at a rate greater than 99%, without concentration dependence in the range of 10 to 100 μg/mL. For more complete data on absorption, distribution, and excretion of pazopanib (8 items in total), please visit the HSDB record page. Metabolites/Metabolites: Primarily metabolized by CYP3A4, with minor metabolism by CYP1A2 and CYP2C8. The metabolites are less active than pazopanib (10 to 20-fold reduced in activity). Its three metabolites are detectable in systemic circulation, accounting for <10% of plasma radioactivity. In vitro studies have shown that pazopanib is primarily metabolized by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Pazopanib (Votrient) is an oral tyrosine kinase inhibitor recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. This study was divided into two parts to investigate the metabolism, distribution, and bioavailability of oral pazopanib tablets in patients with advanced cancer. In Part A, three male patients received a single oral dose of 14C-pazopanib suspension (400 mg, 70 μCi). Two hydroxylated metabolites and one N-demethylated metabolite were detected in circulation, but at low levels, each accounting for <5% of plasma radioactivity. Metabolic pathways observed in human liver microsomes and hepatocytes included monooxygenation, dioxygenation, and possible oxidation to carboxylic acids. Glucuronization of the monooxygenated metabolite was also detected in human hepatocytes. No human-specific Phase I metabolites were observed in either liver microsomes or hepatocyte incubation. However, only one Phase II metabolite, a glucuronide possibly derived from a carboxylic acid metabolite, was observed in human hepatocytes. Its putative precursor was identified in vivo as a significant component (<19%) of bile in cannulated monkeys. In summary, the combined in vitro and in vivo metabolic data indicated no significant differences in metabolism among different species. Pazopanib was metabolized to a low degree in human liver microsomes and hepatocyte incubation, as well as in most preclinical animal models. Pazopanib was metabolized to a higher degree in rabbit and canine hepatocytes than in hepatocytes of other study species. Following oral administration, unmetabolized pazopanib was the predominant component in feces of all species (including humans). Pazopanib (Votrient) is an oral tyrosine kinase inhibitor recently approved for the treatment of renal cell carcinoma and soft tissue sarcoma. This study was divided into two parts to investigate the metabolism, distribution, and bioavailability of oral pazopanib tablets in patients with advanced cancer. In Part A, three male patients received a single oral dose of 14C-pazopanib suspension (400 mg, 70 μCi). The predominant drug-related component in the circulatory system is pazopanib. Two hydroxylated metabolites and one N-demethylated metabolite are also present in the circulatory system, but at extremely low levels, with plasma radioactivity of each metabolite below 5%. ...

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Biological half-life
35 hours. Oral absorption is not the rate-limiting step in plasma elimination.
Pharmacokinetics of pazopanib and/or its dihydrochloride have been studied in various animal species. Terminal elimination half-lives are comparable across animal species (half-life = 2–6 hours), but significantly shorter than those observed in humans (half-life = 21–51 hours).
The mean half-life of pazopanib after administration of the recommended dose of 800 mg is 30.9 hours.

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Pharmacokinetics in rats: Male Sprague-Dawley rats (8 weeks old) were given pazopanib orally at 100 mg/kg: oral bioavailability = 36%, Cmax = 6.8 μM, Tmax = 2.0 h, terminal t₁/₂ = 10.5 h. Intravenous administration of 20 mg/kg: clearance (CL) = 7.2 mL/min/kg, steady-state volume of distribution (Vss) = 1.5 L/kg [1]
- Human plasma protein binding: 99% (equilibrium dialysis [1])
- Metabolism: In human liver microsomes, pazopanib is mainly metabolized by CYP3A4 (70%) and CYP1A2 (20%); urinary excretion of unchanged drug < 8% [1]

Toxicity Summary
Identification and Uses: Pazopanib is a white to pale yellow solid, formulated as film-coated tablets. Pazopanib is a multi-receptor tyrosine kinase inhibitor and belongs to the class of anti-tumor drugs. It is used to treat advanced renal cell carcinoma and advanced soft tissue sarcoma that has previously received chemotherapy. Human Exposure and Toxicity: Serious or fatal hepatotoxicity, manifested as elevated serum transaminase and bilirubin levels, has been reported in patients treated with pazopanib. If hepatotoxicity occurs, the dose of pazopanib should be reduced, or treatment should be paused or permanently discontinued. Pazopanib should be avoided in pregnant women. Although there are currently no adequate and well-controlled studies in pregnant women, animal studies have shown that pazopanib has teratogenic, embryotoxic, fetal toxic, and abortifacient effects. If pazopanib is used during pregnancy, or if a patient becomes pregnant while receiving pazopanib treatment, the potential fetal risks should be explained to the patient. QT interval prolongation, torsades de pointes, and serious or even fatal bleeding events have been reported in patients treated with pazopanib. Furthermore, pazopanib use has been associated with gastrointestinal perforation or fistulas (potentially fatal). Animal studies: Although carcinogenicity studies of pazopanib have not been conducted, in a 13-week mouse study, at a dose of 1000 mg/kg/day, two female mice developed hepatic proliferative lesions (including eosinophilic foci), and one female mouse developed adenoma. Pazopanib can induce fetal teratogenicity (including cardiovascular malformations and delayed ossification), reduced fetal weight, and embryonic death in rats at doses as low as 3 mg/kg/day. In rabbit models, maternal toxicity (weight loss, reduced food intake, and abortion) was observed at doses as low as 30 mg/kg/day, while reduced fetal weight was observed at doses as low as 3 mg/kg/day. Pazopanib also reduces fertility in female rats at a dose of 300 mg/kg. Pre- and post-implantation embryo loss and increased early resorption were observed at doses as low as 10 mg/kg/day. Decreased corpus luteum was observed in monkeys and mice, and ovarian atrophy in rats. While pazopanib did not affect mating or fertility in male rats, decreased spermatogenesis, sperm motility, and epididymal and testicular sperm concentration were observed at doses as low as 100 mg/kg/day for 15 weeks. After 26 weeks of administration, male rats at daily doses of 30 mg/kg or higher exhibited decreased testicular and epididymal weight, testicular atrophy and degeneration, accompanied by azoospermia, decreased sperm count, and cribriform changes in the epididymis. In rat toxicology studies, multiple tissues (bone, teeth, bone marrow, nail bed, reproductive organs, blood tissue, kidneys, adrenal glands, lymph nodes, pituitary gland, and pancreas) were affected, consistent with vascular endothelial growth factor receptor (VEGFR) inhibition and/or VEGF signaling pathway dysregulation, with some effects observed as early as 3 mg/kg/day. Pazopanib has been tested in a series of standard genotoxicity studies. Pazopanib was not found to be mutagenic or chromosomal breakage-inducing in the Ames assay, human peripheral blood lymphocyte chromosome aberration assay, and rat micronucleus assay. Hepatotoxicity: In large clinical trials, abnormalities in routine liver function tests were common in patients treated with pazopanib, with up to half experiencing elevated serum transaminases and approximately one-third experiencing elevated total bilirubin. 8% of patients had ALT and AST values exceeding 5 times the upper limit of normal (ULN), and 1% to 2% experienced simultaneous elevations in both ALT and bilirubin. Rare cases of hepatitis with jaundice have been reported in preliminary trials of pazopanib for various solid tumors. Probability Score: C (Possibly a cause of clinically significant liver injury). Use during Pregnancy and Lactation: ◉ Overview of Use During Lactation: There is currently no information on the clinical use of pazopanib during lactation. Because pazopanib binds to plasma proteins at a rate exceeding 99%, its concentration in breast milk is likely to be very low. However, its half-life is approximately 31 hours, so it may accumulate in infants. The manufacturer recommends discontinuing breastfeeding during pazopanib treatment and for 2 weeks after the last dose.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
>Protein binding is up to 99% in the concentration range of 10-100 μg/mL, regardless of concentration.

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Interactions
Votrient is not suitable for use in combination with other anticancer drugs. Clinical trials of Votrient in combination with pemetrexed and lapatinib were terminated early due to concerns about increased toxicity and mortality. Fatal toxicities observed included pulmonary hemorrhage, gastrointestinal bleeding, and sudden death. Safe and effective combined doses for these regimens have not been determined. In vitro studies have shown that pazopanib is a substrate of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Therefore, drugs that affect Pgp and BCRP may affect the absorption and subsequent clearance of pazopanib. Due to the risk of increased pazopanib exposure, concomitant use with potent Pgp or BCRP inhibitors should be avoided. Alternative concomitant medications with minimal or no inhibition of Pgp or BCRP should be considered. CYP3A4 Inhibitors: Pharmacokinetic interactions (increased peak plasma concentration and area under the plasma concentration-time curve (AUC)) have been observed when pazopanib eye drops are used in combination with ketoconazole (a potent CYP3A4 and Pgp inhibitor), or when pazopanib oral tablets are used in combination with lapatinib (a substrate and weak inhibitor of CYP3A4, Pgp, and BCRP). Concomitant use of pazopanib with potent CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir) should be avoided; if concomitant use cannot be avoided, the dose of pazopanib should be reduced. The manufacturer advises against consuming grapefruit or grapefruit juice concurrently. Concomitant use of Votrient and simvastatin increases the incidence of ALT elevation. In Votrient monotherapy studies, 126/895 (14%) patients not taking statins experienced ALT > 3 times the upper limit of normal, compared to 11/41 (27%) patients taking simvastatin concurrently. If ALT elevation occurs in patients taking simvastatin concurrently, follow the Votrient dosage guidelines or consider alternative medications to Votrient. Alternatively, consider discontinuing simvastatin. There is currently insufficient data to assess the risks of concomitant use of other statins and Votrient. For more complete data on interactions of pazopanib (one of 13), please visit the HSDB records page.

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In vitro cytotoxicity: In normal human renal proximal tubular cells (RPTEC), osteoblasts (hFOB 1.19), and retinal pigment epithelial cells (ARPE-19), pazopanib (at concentrations up to 10 μM, for 72 hours) showed >80% cell viability, indicating low non-specific toxicity [1][2][3].
Acute in vivo toxicity: Rats administered pazopanib 100 mg/kg orally for 28 days developed mild hypertension (12% of animals had systolic blood pressure <25 mmHg), but no liver or kidney damage was observed (ALT/AST/creatinine were normal). [1]
-Tissue-specific toxicity: Mice treated with pazopanib 5–20 mg/kg (orally, for 35 days) did not develop osteonecrosis (MG-63 model) or retinal tissue damage (OIR model) [2][3]

[1]. J Med Chem . 2008 Aug 14;51(15):4632-40.

[2]. J Orthop Res . 2012 Sep;30(9):1493-8.

[3]. Retina . 2012 Sep;32(8):1652-63.

Therapeutic Uses
Votrient is indicated for the treatment of patients with advanced renal cell carcinoma (RCC). /US Product Label/
Votrient is indicated for the treatment of patients with advanced soft tissue sarcoma (STS) who have previously received chemotherapy. /US Product Label/
Usage Restrictions: The efficacy of Votrient in treating patients with lipocyte soft tissue sarcoma (STS) or gastrointestinal stromal tumors has not been established.
Exploratory Treatment: Pazopanib has been evaluated for its ability to inhibit the growth of various human tumor cell lines (HT-29 (colon cancer), MDA-MB-468 (breast cancer), PC3 (prostate cancer), and A375P (melanoma)) and normal human fibroblasts (HFF) grown in serum-containing medium. Pazopanib showed an IC50 value of 1.01 μM for inhibiting HFF cell proliferation, and had no effect on the proliferation of four tumor cell lines at the highest tested concentration (30 μM). To further investigate whether pazopanib can directly regulate tumor cell proliferation, we performed cell proliferation assays on 282 human cell lines. Of these, 281 were tumor cell lines derived from different tissue types, and one was a non-transformed breast cell line. The IC50 values for all cell lines ranged from 0.01 μM to >10 μM. Only seven cell lines had IC50 values <1 μM: GDM1 (acute myeloid leukemia); ARH-77 (multiple myeloma); NCI-H716 (colon cancer); G402 (renal leiomyocyte-derived tumor); CGTH-W-1 (thyroid cancer); A204 (rhabdomyosarcoma); and CML-T1 (chronic myeloid leukemia). Therefore, pazopanib showed weak or no inhibitory effect on cell proliferation in most human cell lines tested in vitro. Thus, the antitumor activity of pazopanib likely derives from its antiproliferative effect on endothelial cells.

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Drug Warning
/Black Box Warning/ Warning: Hepatotoxicity.
Severe and even fatal hepatotoxicity has been observed in clinical trials. Liver function should be monitored, and medication should be paused, reduced, or discontinued as advised. Severe or fatal hepatotoxicity, manifested as elevated serum transaminase (ALT (SGPT), AST (SGOT)) and bilirubin levels, has been reported in patients treated with pazopanib. The majority (92.5%) of transaminase elevations (of any grade) occurred within the first 18 weeks of treatment. In a randomized, placebo-controlled study in patients with renal cell carcinoma (VEG105192), approximately 18% and 4% of patients treated with pazopanib experienced ALT levels exceeding 3 times and 10 times the upper limit of normal (ULN), respectively. In cases without significant elevations (exceeding 3 times the ULN), approximately 2% of patients treated with pazopanib experienced simultaneous elevations of both ALT (exceeding 3 times the ULN) and bilirubin (exceeding 2 times the ULN). An analysis of data from 11 studies involving 977 patients receiving pazopanib monotherapy showed that approximately 0.2% of patients treated with pazopanib died (due to disease progression and liver failure). These patients had various tumor types (including 586 cases of renal cell carcinoma). Because pazopanib inhibits uridine diphosphate glucuronide transferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin to clear bilirubin), patients with insufficient bilirubin glucuronidation (e.g., Gilbert's syndrome) may experience a mild increase in indirect (unconjugated) bilirubin. Liver function tests should be performed before starting pazopanib and at least every 4 weeks for at least 4 months after starting treatment, or as clinically necessary, and thereafter periodically. If hepatotoxicity occurs, the pazopanib dose should be reduced, or treatment should be paused or permanently discontinued. FDA Pregnancy Risk Category: D/Positive Evidence of Risk. Human studies, investigational data, or post-marketing data have shown a risk to the fetus. However, the potential benefits of using this drug may outweigh the potential risks. For example, this drug may be acceptable in life-threatening situations or when patients have serious illness and other safer medications are unavailable or ineffective. Patients receiving pazopanib have reported QT interval prolongation and torsades de pointes. In the VEG105192 study, approximately 1% of patients receiving pazopanib experienced QT interval prolongation (500–549 ms), compared to approximately 0% of patients receiving placebo. In a pooled analysis of data from three studies, including 55,815 patients with renal cell carcinoma, approximately 2% of patients receiving pazopanib experienced QT interval prolongation (≥500 ms), while less than 1% experienced torsades de pointes. Pazopanib should be used with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmic drugs or other medications that prolong the QT interval, and patients with relevant pre-existing cardiac conditions. Electrocardiograms should be monitored before starting pazopanib and regularly during treatment; serum electrolytes (e.g., calcium, magnesium, potassium) should be maintained within the normal range. For more drug warnings (complete) data (23 in total) for pazopanib, please visit the HSDB record page. Pharmacodynamics Pazopanib is a synthetic indazole pyrimidine with a steady-state concentration of >15 μg/ml. This concentration is sufficient to observe maximum inhibition of VEGFR2 phosphorylation and some antitumor activity (the concentration required to inhibit the receptor is 0.01-0.084 μmol/L). Patients receiving treatment may observe reduced tumor blood flow, increased tumor cell apoptosis, inhibited tumor growth, reduced tumor interstitial fluid pressure, and hypoxia in cancer cells. Pazopanib (GW 786034; Votrient) is a multi-target tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma (RCC) and soft tissue sarcoma[1].
- Its mechanism of action includes binding to the ATP-binding pockets of VEGFR, PDGFR, and c-Kit, inhibiting the activation of tyrosine kinases and downstream signaling pathways (ERK/AKT), thereby inhibiting angiogenesis, tumor growth, and vascular leakage [1][2][3].
- It has shown preclinical efficacy in osteosarcoma (MG-63 model) and retinal neovascularization (OIR model), supporting its potential application in orthopedic and ophthalmic diseases [2][3]. It was approved by the FDA in 2009 for the treatment of advanced renal cell carcinoma; dose adjustment is recommended for patients with moderate hepatic impairment [1].

C21H23N7O2S

437.52

437.163

C, 57.65; H, 5.30; N, 22.41; O, 7.31; S, 7.33

444731-52-6

Pazopanib Hydrochloride;635702-64-6;Pazopanib-d6;1219592-01-4;Pazopanib-13C,d3;1261734-88-6

10113978

white solid powder

1.4±0.1 g/cm3

728.8±70.0 °C at 760 mmHg

285-289°C (dec.)

394.6±35.7 °C

0.0±2.4 mmHg at 25°C

1.702

1.98

2

8

5

31

717

0

S(C1C([H])=C(C([H])=C([H])C=1C([H])([H])[H])N([H])C1=NC([H])=C([H])C(=N1)N(C([H])([H])[H])C1C([H])=C([H])C2=C(C([H])([H])[H])N(C([H])([H])[H])N=C2C=1[H])(N([H])[H])(=O)=O

CUIHSIWYWATEQL-UHFFFAOYSA-N

InChI=1S/C21H23N7O2S/c1-13-5-6-15(11-19(13)31(22,29)30)24-21-23-10-9-20(25-21)27(3)16-7-8-17-14(2)28(4)26-18(17)12-16/h5-12H,1-4H3,(H2,22,29,30)(H,23,24,25)

5-[[4-[(2,3-dimethylindazol-6-yl)-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide

GW-78603; GW78603; GW 78603; GW-786034; GW786034; GW 786034; Pazopanib; trade name: Votrient

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 (5.71 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 2: ≥ 2.5 mg/mL (5.71 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 3: ≥ 0.43 mg/mL (0.98 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 4: ≥ 0.43 mg/mL (0.98 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
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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 (Please use freshly prepared in vivo formulations for optimal results.)