CYP3A (Cytochrome P450 3A): Schisandrin A is an inhibitor of CYP3A activity. (IC50 = 6.60 μM; Ki = 5.83 μM) [1]

With an IC50 of 6.60 μM, schisandrin A (Sch A) potently inhibits the microsomal midazolam 1-hydroxylation process mediated by CYP3A. The dilution assay graph displays the recovery of enzyme activity in the presence and absence of Schisandrin A. Using the Dixon plot, the Ki value of Schisandrin A was found to be 5.83 μM. The research discovered that Schisandrin A deactivated the midazolam 1-hydroxylation activity of rat liver microsomes in a concentration- and time-dependent manner when NADPH was present. Schisandrin A's kappa and Ki are calculated to be 4.51 μM and 0.134/min, respectively [1].

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Inhibition of CYP3A Activity: Schisandrin A inhibited CYP3A-mediated 1'-hydroxylation of midazolam in rat liver microsomes in a concentration-dependent manner, with an IC50 value of 6.60 μM. [1]
- Reversible Inhibition Kinetics: Schisandrin A was found to be a mixed noncompetitive inhibitor of CYP3A, with a Ki value of 5.83 μM. A dilution assay showed that after 100-fold dilution, the inhibitory activity of Schisandrin A recovered to 91% of the control, indicating that the inhibition is primarily reversible. [1]
- Time- and Concentration-Dependent Inactivation: Schisandrin A also exhibited time- and concentration-dependent inactivation of CYP3A activity. The inactivation parameters were: KI = 4.51 μM (the concentration of inhibitor resulting in half-maximal inactivation rate), and kinact = 0.134 /min (the maximal inactivation rate constant). [1]

In a concentration-dependent manner, schisandrin A (SchA) markedly reduced the CYP3A activity of rat liver microsomes as well as the Vmax value of every group. Schisandrin A suppresses CYP3A activity, as seen by the double reciprocal plot and the quadratic plot, with an apparent Ki value of 30.67 mg/kg. When compared to the Negative group, Schisandrin A also dramatically decreased the plasma concentrations of 1-hydroxymidazolam in each Schisandrin A treatment group, bringing them down to levels comparable to those in the Positive group [2].

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In male Sprague-Dawley rats, continuous oral administration of Schisandrin A (8, 16, or 32 mg/kg, once daily for 3 days) produced concentration-dependent inhibition of hepatic microsomal CYP3A activity. The formation of 1'-hydroxymidazolam in liver microsomes was significantly reduced compared to the vehicle-treated negative control group: 1185.2 ± 85.64 ng/mg protein (8 mg/kg, P = 0.000), 1051.6 ± 173.58 ng/mg protein (16 mg/kg, P = 0.001), and 943.73 ± 303.17 ng/mg protein (32 mg/kg, P = 0.010), versus 1488.6 ± 136.06 ng/mg protein in the control group. [2]
Schisandrin A treatment increased the maximum plasma concentration (Cₘₐₓ) of orally administered midazolam (a CYP3A substrate) in a concentration-dependent manner: 1.757 ± 0.840 mg/L (8 mg/kg, P > 0.05), 2.159 ± 1.202 mg/L (16 mg/kg, P < 0.05), and 2.202 ± 0.747 mg/L (32 mg/kg, P < 0.05), compared to 1.559 ± 0.619 mg/L in the control group. The area under the concentration-time curve (AUC₀₋∞) of midazolam was also significantly increased: 1.665 ± 0.701 mg·h/L (8 mg/kg, P < 0.05), 2.225 ± 1.396 mg·h/L (16 mg/kg, P < 0.05), and 2.475 ± 1.427 mg·h/L (32 mg/kg, P < 0.01), versus 1.186 ± 0.348 mg·h/L in the control group. [2]
Conversely, Schisandrin A significantly decreased the Cₘₐₓ and AUC of the midazolam metabolite 1'-hydroxymidazolam. For the 32 mg/kg group, Cₘₐₓ was 0.364 ± 0.163 mg/L (P < 0.01) compared to 0.544 ± 0.133 mg/L in the control group, and AUC₀₋∞ was 0.443 ± 0.165 mg·h/L (P < 0.05) compared to 0.711 ± 0.184 mg·h/L in the control group. [2]
Kinetic analysis of microsomal data showed that Schisandrin A decreased the Vₘₐₓ of midazolam metabolism in a concentration-dependent manner (0.913, 0.888, 0.835, and 0.669 nM/min/mg for control, 8, 16, and 32 mg/kg groups, respectively), while Kₘ values remained relatively unchanged (14.58, 17.53, 18.13, and 20.17 μM, respectively), indicating non-competitive inhibition. [2]

CYP3A Activity Assay in Rat Liver Microsomes: Rat liver microsomes were prepared. CYP3A activity was measured by analyzing the formation of 1'-hydroxy midazolam from midazolam using high-performance liquid chromatography (HPLC). Midazolam (40 μM) was incubated with varying concentrations of Schisandrin A (0.1, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, 256, or 512 μM) and rat liver microsomes (0.25 mg/mL) in a final volume of 200 μL. The reaction was initiated by the addition of NADPH and terminated after 10 minutes. The concentration of 1'-hydroxy midazolam was quantified by HPLC. [1]
- Reversible Inhibition Determination (Dilution Assay): To determine the reversibility of inhibition, Schisandrin A (40 μM) was pre-incubated with rat liver microsomes (0.25 mg/mL) and NADPH for 30 minutes. The mixture was then diluted 100-fold with 0.1 M phosphate buffer (pH 7.4) containing 40 μM midazolam and 1.0 mM NADPH. The residual CYP3A activity was measured after a 10-minute incubation and compared to control samples that were similarly treated without the inhibitor. [1]
- Mechanism-Based Inactivation Assay: To assess time- and concentration-dependent inactivation, Schisandrin A (2.5, 5, 10, 20, 40, or 80 μM) was pre-incubated with rat liver microsomes (0.25 mg/mL) and NADPH (1.0 mM) at 37°C for 0, 2.5, 5, 10, 15, 20, 30, or 45 minutes. Aliquots (5 μL) of the pre-incubation mixture were then diluted 100-fold into a second reaction mixture containing 40 μM midazolam and 1.0 mM NADPH. After a 10-minute incubation, the remaining CYP3A activity was determined by HPLC. [1]

Male Sprague-Dawley rats (2-3 months old, 250-280 g) were housed under controlled conditions (22 ± 2°C, 12-hour light/dark cycle) and acclimated for 5-7 days before study initiation. Rats were randomly divided into five groups (n = 16 per group): negative control (vehicle), Schisandrin A 8 mg/kg, Schisandrin A 16 mg/kg, Schisandrin A 32 mg/kg, and positive control (ketoconazole 75 mg/kg). All treatments were administered intragastrically once daily for three consecutive days. [2]
On day 3, eight rats from each group were sacrificed 30 minutes after the last drug treatment. Livers were collected for microsome preparation. The remaining eight rats from each group were anesthetized with intraperitoneal pentobarbital (30 mg/kg). Thirty minutes after the last drug treatment, midazolam (20 mg/kg) was administered via single-pass duodenum perfusion. Blood samples were collected from the femoral artery at 0, 2, 5, 10, 20, 30, 60, 90, 120, and 180 minutes after midazolam administration. Plasma was separated by centrifugation and stored at -80°C until analysis. [2]

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Male Sprague-Dawley rats (2-3 months old, 250-280 g) were housed under controlled conditions (22 ± 2°C, 12-hour light/dark cycle) and acclimated for 5-7 days before study initiation. Rats were randomly divided into five groups (n = 16 per group): negative control (vehicle), Schisandrin A 8 mg/kg, Schisandrin A 16 mg/kg, Schisandrin A 32 mg/kg, and positive control (ketoconazole 75 mg/kg). All treatments were administered intragastrically once daily for three consecutive days. [2]
On day 3, eight rats from each group were sacrificed 30 minutes after the last drug treatment. Livers were collected for microsome preparation. The remaining eight rats from each group were anesthetized with intraperitoneal pentobarbital (30 mg/kg). Thirty minutes after the last drug treatment, midazolam (20 mg/kg) was administered via single-pass duodenum perfusion. Blood samples were collected from the femoral artery at 0, 2, 5, 10, 20, 30, 60, 90, 120, and 180 minutes after midazolam administration. Plasma was separated by centrifugation and stored at -80°C until analysis. [2]

Schisandrin A (8, 16, or 32 mg/kg, once daily for 3 days) significantly altered the pharmacokinetics of the CYP3A probe substrate midazolam (20 mg/kg, oral) in rats. For midazolam, Cₘₐₓ increased from 1.559 ± 0.619 mg/L (control) to 2.202 ± 0.747 mg/L in the 32 mg/kg Schisandrin A group (P < 0.05). AUC₀₋∞ increased from 1.186 ± 0.348 mg·h/L (control) to 2.475 ± 1.427 mg·h/L in the 32 mg/kg group (P < 0.01). Apparent clearance (CLz) decreased from 17.076 ± 6.001 L/h/kg (control) to 11.505 ± 6.025 L/h/kg in the 32 mg/kg group (P > 0.05). [2]
For the metabolite 1'-hydroxymidazolam, Cₘₐₓ decreased from 0.544 ± 0.133 mg/L (control) to 0.364 ± 0.163 mg/L in the 32 mg/kg group (P < 0.01). AUC₀₋∞ decreased from 0.711 ± 0.184 mg·h/L (control) to 0.443 ± 0.165 mg·h/L in the 32 mg/kg group (P < 0.05). The elimination half-life (t₁/₂) of 1'-hydroxymidazolam decreased from 64.104 ± 16.243 minutes (control) to 44.891 ± 10.484 minutes in the 8 mg/kg group (P < 0.01) and to 49.913 ± 13.999 minutes in the 16 mg/kg group (P < 0.05). [2]

[1]. Inhibitory effects of Schisandrin A and Schisandrin B on CYP3A activity. Methods Find Exp Clin Pharmacol. 2010 Apr;32(3):163-9.

[2]. Inhibitory effects of continuous ingestion of Schisandrin A on CYP3A in the rat. Basic Clin Pharmacol Toxicol. 2012 Feb;110(2):187-92.

Schisandrin A is a tannin. It has been reported to be found in Schisandra chinensis, Schisandra chinensis, and other organisms with relevant data. See also: Schisandra chinensis fruit (partial); deoxyschisandrin (note moved to).

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Background: Schisandrin A (Sch A) is one of the most abundant active dibenzocyclooctadiene derivatives isolated from Schisandra sphenanthera. It is a known component of the traditional Chinese herbal medicine Schisandra sphenanthera extract (Sch E), which has been clinically used for the treatment of viral and chemical hepatitis. [1]
- Drug Interaction Potential: The study demonstrates that Schisandrin A is a potent inhibitor of CYP3A. Since CYP3A is responsible for the metabolism of over 50% of clinically used drugs (including tacrolimus and midazolam), co-administration of Schisandrin A-containing products with CYP3A substrates could significantly alter the pharmacokinetics of those drugs, potentially leading to increased drug exposure and toxicity. [1]

C24H32O6

416.514

416.219

61281-38-7

Schisandrin;7432-28-2

155256

White to off-white solid powder

1.1±0.1 g/cm3

544.2±50.0 °C at 760 mmHg

114 °C

215.6±30.0 °C

0.0±1.4 mmHg at 25°C

1.520

5.87

0

6

6

30

484

2

O(C([H])([H])[H])C1C(=C(C([H])=C2C=1C1=C(C(=C(C([H])=C1C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C2([H])[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H])OC([H])([H])[H]

JEJFTTRHGBKKEI-OKILXGFUSA-N

InChI=1S/C24H32O6/c1-13-9-15-11-17(25-3)21(27-5)23(29-7)19(15)20-16(10-14(13)2)12-18(26-4)22(28-6)24(20)30-8/h11-14H,9-10H2,1-8H3/t13-,14+

(9S,10R)-3,4,5,14,15,16-hexamethoxy-9,10-dimethyltricyclo[10.4.0.02,7]hexadeca-1(16),2,4,6,12,14-hexaene

Deoxyschizandrin Schizandrin A Deoxyschisandrin

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)

DMSO : ~50 mg/mL (~120.05 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.00 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 (6.00 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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 (6.00 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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 (Please use freshly prepared in vivo formulations for optimal results.)