Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. Animal
2.3. LC-MS/MS Analysis and Method Validation
2.4. HPLC Analysis and Method Validation
2.5. Preparation of Plasma, Live-Homogenate and Intestinal Sac Fluid Samples
2.6. Plasma Pharmacokinetics
2.7. Intestinal Sac Absorption Test In Vitro (Everted Intestinal Sac Method)
2.8. Liver Homogenate Metabolism
2.9. Stability of Azalomycin F in Plasma and Whole Blood
2.10. Plasma Protein Binding Assay
2.11. Pharmacokinetic Parameters and Statistical Analysis
3. Results
3.1. Method Validation
3.2. Pharmacokinetic Parameters
3.3. Intestinal Sac Absorption Test In Vitro
3.4. Liver Homogenate Metabolism Experiment
3.5. The Stability of Azalomycin F in Plasma and Whole Blood
3.6. Plasma Protein Binding Assay
4. Discussion
5. Conclusions
- (a)
- A rapid, specific and sensitive analysis method was developed using UPLC-MS/MS technology for the quantitative determination of azalomycin F in rat plasma, and the HPLC analysis for the quantitative determination of azalomycin F in the liver homogenate, intestinal sac fluid samples, and plasma protein binding of rats, in vitro, was also established.
- (b)
- After administrated by gavage, azalomycin F can be absorbed by intestinal tract at low degree and relatively slow rate, and its absolute bioavailability is very low. This indicated that azalomycin F is suitable for intravenous administration when used for systemic diseases, while oral administration can be used for the treatment on the diseases of gastrointestinal tract.
- (c)
- The low oral absolute bioavailability of azalomycin F is likely due to the combined effects of its low absorption efficiency in the intestinal tract, the bile excretion before the absorption into the systemic blood, and the degradation from both intestinal mucosa, during its absorption, and gut microorganisms, before fecal excretion. This may be also the reason that the acute toxicity of azalomycin F by gavage was much lower than that by intravenous administration.
- (d)
- After administrated by intravenous injection or absorbed from the intestinal tract, azalomycin F can be rapidly distributed into the tissues and/or intracellular fluid from the blood of rats.
- (e)
- Azalomycin F presents plasma protein binding ratios of more than 90% and is stable in plasma, whole blood, and liver homogenate. The last is likely due to the binding between azalomycin F and α1-acidic glycoprotein in the liver homogenate and plasma.
- (f)
- Biliary excretion is the major pathway of eliminating azalomycin F in the form of a prototype drug, and no prototype drug was detected in the urine, while other elimination routes remain unclear. Therefore, the metabolic sites and identifications of azalomycin F metabolites should be further explored for.
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Group Name | Detail a |
---|---|
Blank | 10 μL methanol + 1 mL liver homogenate |
Negative control | 10 μL 10 mg/mL Azalomycin F solution + 1 mL Tris-HCl-KCl solution |
Positive control | 10 μL 10 mg/mL phenacetin solution + 1 mL liver homogenate |
Experimental group | 10 μL 10 mg/mL Azalomycin F solution + 1 mL liver homogenate |
Parameters | Units | 26.4 mg/kg (i.g.) | 2.2 mg/kg (i.v.) |
---|---|---|---|
AUC(0-t) | mg/L∙h | 1.380 ± 0.544 | 6.474 ± 0.886 |
AUC(0-∞) | mg/L∙h | 1.873 ± 1.007 | 6.541 ± 0.851 |
VZ | L/kg | 1.691 ± 0.359 | 0.434 ± 0.679 |
t1/2 | h | 3.329 ± 1.477 | 0.945 ± 1.516 |
CL | L/h/kg | 0.412 ± 0.207 | 0.341 ± 0.050 |
MRT(0-∞) | h | 6.458 ± 2.333 | 0.490 ± 0.435 |
Cmax | mg/L | 0.325 ± 0.200 | - |
Tmax | h | 3 | - |
C0 b | mg/L | - | 4.561 |
Ka c | 1/h | 0.168 | - |
F | % | 2.386 ± 1.283 | - |
Segment I | Segment II | Segment III | Segment IV | Total | |
---|---|---|---|---|---|
Absorptive amount (mg) | 0.021 ± 0.009 | 0.022 ± 0.015 | 0.025 ± 0.022 | 0.022 ± 0.011 | 0.090 ± 0.048 |
Absorption ratio (%) | 0.21 ± 0.09 | 0.23 ± 0.15 | 0.26 ± 0.24 | 0.22 ± 0.11 | 0.91 ± 0.51 |
Added Concentration (mg/mL) | Concentration in Plasma (mg/mL) | Concentration in Buffer (mg/mL) | Protein-Binding Ratio (%) |
---|---|---|---|
0.025 | 0.495 ± 0.055 | 0.015 ± 0.001 | 96.88 ± 0.63 |
0.05 | 0.675 ± 0.043 | 0.047 ± 0.004 | 92.96 ± 0.76 |
0.1 | 1.062 ± 0.115 | 0.098 ± 0.008 | 90.65 ± 0.92 |
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He, S.; Zhao, W.; Li, P.; Tu, W.; Hong, K.; Zhang, D.; Zhang, T.; Yuan, G. Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats. Molecules 2021, 26, 6464. https://doi.org/10.3390/molecules26216464
He S, Zhao W, Li P, Tu W, Hong K, Zhang D, Zhang T, Yuan G. Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats. Molecules. 2021; 26(21):6464. https://doi.org/10.3390/molecules26216464
Chicago/Turabian StyleHe, Su, Wenjia Zhao, Peibo Li, Wenqing Tu, Kui Hong, Duoduo Zhang, Tongke Zhang, and Ganjun Yuan. 2021. "Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats" Molecules 26, no. 21: 6464. https://doi.org/10.3390/molecules26216464