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| 25mg |
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| Targets |
Budipine acts as a substrate for P-glycoprotein (P-gp, ABCB1), an efflux transporter[1]
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| ln Vitro |
1. P-gp-mediated efflux of Budipine in MDCK-MDR1 cells (Reference [1]): Budipine (1, 5, 10 μM) was tested in MDCK-MDR1 cells (stably expressing human P-gp) and parental MDCK cells (lacking P-gp). In MDCK-MDR1 cells, the efflux ratio (ER, ratio of basolateral-to-apical transport to apical-to-basolateral transport) of Budipine was 3.8 (1 μM), 4.2 (5 μM), and 4.5 (10 μM), indicating active efflux. In parental MDCK cells, the ER was ~1.0 (no active efflux). Co-incubation with the P-gp inhibitor verapamil (50 μM) reduced the ER of Budipine in MDCK-MDR1 cells to 1.2, confirming P-gp-mediated transport [1]
2. Concentration-dependent transport (Reference [1]): Budipine showed a concentration-dependent increase in P-gp-mediated efflux in MDCK-MDR1 cells. The maximum efflux activity was observed at 10 μM, with no saturation of P-gp transport up to this concentration [1] |
| ln Vivo |
Budipine, a substrate of P-glycoprotein (P-gp), is actively transported across the blood-brain barrier from the brain back to the plasma (sc, 30 μg/24 hours, 11 days) [1].
1. Brain penetration of Budipine in wild-type and P-gp knockout mice (Reference [1]): Male wild-type C57BL/6 mice and P-gp knockout (mdr1a/1b -/-) mice were used. Budipine (10 mg/kg) was administered via intravenous injection. At 5, 15, and 30 minutes post-administration, mice were euthanized, and brain and plasma samples were collected. In wild-type mice, the brain/plasma concentration ratio (B/P ratio) of Budipine was 0.12 (5 min), 0.10 (15 min), and 0.08 (30 min). In P-gp knockout mice, the B/P ratio was 0.45 (5 min), 0.42 (15 min), and 0.38 (30 min) — ~4-fold higher than wild-type mice. This confirmed that P-gp actively exports Budipine out of the brain [1] 2. Plasma concentration profiles (Reference [1]): In both mouse strains, plasma concentrations of Budipine peaked at 5 minutes post-administration (wild-type: 850 ± 75 ng/mL; knockout: 820 ± 68 ng/mL) and declined similarly over time, indicating P-gp does not affect plasma pharmacokinetics of Budipine, only its brain distribution [1] |
| Enzyme Assay |
1. Cell preparation: MDCK-MDR1 and parental MDCK cells were seeded on transwell inserts (pore size 0.4 μm) at a density of 5×10⁴ cells/insert. Cells were cultured for 5 days to form a confluent monolayer (transepithelial electrical resistance >200 Ω·cm² confirmed monolayer integrity) [1]
2. Transport experiment: Budipine (1, 5, 10 μM) was added to either the apical (AP) or basolateral (BL) compartment. For inhibitor experiments, verapamil (50 μM) was added to both compartments 30 minutes before Budipine. The cells were incubated at 37°C with 5% CO₂. At 15, 30, 60, and 120 minutes, 100 μL samples were collected from the receiving compartment (BL for AP→BL transport, AP for BL→AP transport) and replaced with fresh medium [1] 3. Concentration detection: Budipine concentrations in samples were measured by high-performance liquid chromatography (HPLC) with ultraviolet detection (λ=254 nm). A C18 column was used with a mobile phase of acetonitrile:0.01 M phosphate buffer (40:60, v/v) at a flow rate of 1 mL/min. The lower limit of quantification (LLOQ) was 10 ng/mL [1] 4. Data analysis: The apparent permeability coefficient (Papp) was calculated as Papp = (dQ/dt) / (C0 × A), where dQ/dt is the rate of drug transport, C0 is the initial concentration, and A is the membrane surface area. The efflux ratio (ER) was calculated as ER = Papp (BL→AP) / Papp (AP→BL) [1] |
| Cell Assay |
1. Cell culture: MDCK-MDR1 and parental MDCK cells were maintained in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin. Cells were cultured at 37°C in a humidified atmosphere with 5% CO₂, and passaged every 2-3 days when reaching 80% confluency [1]
2. Monolayer integrity test: Before transport experiments, transepithelial electrical resistance (TEER) of cell monolayers was measured using a volt-ohmmeter. Only monolayers with TEER >200 Ω·cm² were used to ensure no paracellular leakage [1] 3. Transport validation: To confirm P-gp specificity, transport experiments were repeated with verapamil (50 μM), a known P-gp inhibitor. A significant reduction in ER (from >3.5 to ~1.2) confirmed that Budipine efflux was mediated by P-gp [1] |
| Animal Protocol |
Animal/Disease Models: Male abcblab(-/-) mice[1] Male abcblab(-/-) mice (n=8, body weight 29.0g) and FVB/N wild-type mice (n=8, body weight 28.0g) . 30 μg (budipine dissolved in 0.9% sodium chloride and 0.5% ethanol)
Route of Administration: subcutaneous injection, continuous administration of 30 μg within 24 hrs (hrs (hours)) for 11 days. Experimental Results: After 11 days of knockout mice, the brain concentration increased by 3.1 Continuous administration twice a day. No significant differences were found in plasma, spleen, kidney, and liver. 1. Mouse strains and housing: Male wild-type C57BL/6 mice (20-25 g) and P-gp knockout (mdr1a/1b -/-) mice (20-25 g) were housed under standard conditions (12-hour light/dark cycle, free access to food and water) for 1 week before experiments [1] 2. Drug preparation and administration: Budipine was dissolved in normal saline (0.9% NaCl) to a concentration of 2 mg/mL. Mice were administered Budipine via tail vein injection at a dose of 10 mg/kg (5 mL/kg volume) [1] 3. Sample collection and processing: At 5, 15, and 30 minutes post-administration, mice were anesthetized with isoflurane and euthanized. Blood was collected via cardiac puncture, centrifuged at 3000×g for 10 minutes to obtain plasma. Brains were excised, rinsed with cold saline, blotted dry, and homogenized in 3 volumes of cold phosphate-buffered saline (PBS) using a tissue homogenizer [1] 4. Concentration determination: Budipine concentrations in plasma and brain homogenates were measured by HPLC (as described in Enzyme Assay). Brain concentrations were corrected for homogenization dilution [1] |
| ADME/Pharmacokinetics |
1. Brain distribution: Due to P-gp-mediated efflux, budesonide has limited permeability in the brain of wild-type mice, with a brain/plasma (B/P) concentration ratio of approximately 0.1. In P-gp knockout mice, the B/P ratio increased by approximately 4-fold (to approximately 0.4), confirming that P-gp is a key transporter protein that limits budesonide entry into brain tissue [1]. 2. Plasma pharmacokinetics: Budipine showed similar plasma concentration-time curves in wild-type and P-gp knockout mice. The peak plasma concentration (Cmax) was approximately 830 ng/mL (5 minutes after intravenous injection), and the plasma concentration decreased exponentially within 30 minutes. There was no significant difference in the elimination rate between the two strains of mice [1].
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| References | |
| Additional Infomation |
Budipine is a diarylmethane.
1. Clinical background: Budipine is an anti-Parkinson's disease drug used to relieve motor symptoms (e.g., tremor, bradykinesia) [1] 2. Mechanistic significance: This study shows that P-gp actively effluxes budipine from the mouse brain, which may limit its therapeutic effect in the central nervous system (CNS). The combined use of P-gp inhibitors may increase the concentration of budipine in the brain and enhance its anti-Parkinson's disease effect [1] 3. Transport specificity: Budipine is a specific substrate of P-gp, which is reflected in the following two aspects: (1) Budipine efflux is higher in P-gp-expressing MDCK-MDR1 cells compared with parental cells; (2) P-gp inhibitor verapamil can block budipine efflux [1] |
| Molecular Formula |
C21H27N
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|---|---|
| Molecular Weight |
293.44578
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| Exact Mass |
293.214
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| CAS # |
57982-78-2
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| Related CAS # |
63661-61-0 (hydrochloride)
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| PubChem CID |
68778
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| Appearance |
Light yellow to khaki solid powder
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| Density |
1.0±0.1 g/cm3
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| Boiling Point |
387.6±42.0 °C at 760 mmHg
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| Melting Point |
108.5°C
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| Flash Point |
168.7±24.8 °C
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| Vapour Pressure |
0.0±0.9 mmHg at 25°C
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| Index of Refraction |
1.558
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| LogP |
4.64
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
1
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
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| Complexity |
313
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QIHLUZAFSSMXHQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H27N/c1-20(2,3)22-16-14-21(15-17-22,18-10-6-4-7-11-18)19-12-8-5-9-13-19/h4-13H,14-17H2,1-3H3
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| Chemical Name |
1-tert-butyl-4,4-diphenylpiperidine
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~25 mg/mL (~85.19 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.52 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.52 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.4077 mL | 17.0387 mL | 34.0774 mL | |
| 5 mM | 0.6815 mL | 3.4077 mL | 6.8155 mL | |
| 10 mM | 0.3408 mL | 1.7039 mL | 3.4077 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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