Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog
Abstract
1. Introduction
2. Materials and Methods
2.1. Test Compounds and Animals
2.2. Plasma Protein Binding
2.3. Pharmacokinetic Studies
2.3.1. Pharmacokinetic Studies in Mice
2.3.2. Pharmacokinetic Studies in Rats
2.3.3. Pharmacokinetic Studies in Monkeys
2.3.4. Allometric Scaling
2.4. LC-MS/MS Analysis
2.5. Pharmacokinetic Data Analysis
3. Results and Discussion
3.1. Plasma Protein Binding
3.2. Pharmacokinetic Studies
3.3. Dose Proportionality
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
NCA | Noncompartmental analysis |
Clast | Last measurable concentration |
AUClast | Area under the curve from time zero to last measurable concentration-time point |
AUC0–inf | Area under the curve from time zero extrapolated to infinity |
CL | Systemic clearance |
Vd | Volume of distribution |
MRTinf | Mean residence time from time zero to infinity |
PK | Pharmacokinetics |
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Study | Species | Strain | Gender | Compound | Dose | No. of Animals | Time Points | Sampling Procedure |
---|---|---|---|---|---|---|---|---|
1 | Mouse | Athymic nude | Male | MTM | 2 mg/kg | 15 | 5 min, 30 min, 1.5 h, 3 h, 6 h | Destructive |
MTMSA-Trp | 2 mg/kg | 15 | ||||||
2 | Rat | Sprague Dawley | Male | MTM | 0.5 mg/kg | 6 | 5 min, 20 min, 1 h, 3 h, 6 h, 9 h | Serial |
MTMSA-Trp | 0.5 mg/kg | 6 | ||||||
3 | Monkey | Cynomolgus | Male | MTM | 6.94 µg/kg | 1 | 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h | Serial |
MTMSA-Trp | 1.34 µg/kg | 1 | 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h | |||||
4 | Monkey | Cynomolgus | Male | MTM | 13.18 µg/kg | 1 | 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h | Serial |
MTMSA-Trp | 4.19 µg/kg | 1 | 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h | |||||
5 | Mouse | Athymic nude | Male | MTM and MTMSA-Trp 1 | 69 µg/kg 2 | 9 | 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h | Serial |
6 | Rat | Sprague Dawley | Male | MTM and MTMSA-Trp 1 | 28 µg/kg 2 | 9 | Serial | |
7 | Mouse | Athymic nude | Female | MTMSA-Trp | 1 mg/kg | 12 | 5 min, 30 min, 2 h, 5 h | Destructive |
3 mg/kg | 12 | |||||||
10 mg/kg | 12 | |||||||
8 | Mouse | Athymic nude | Female | MTMSA-Trp | 0.3 mg/kg | 9 | 10 min, 20 min, 30 min, 45 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h | Serial |
1 mg/kg | 9 | 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h | ||||||
3 mg/kg | 9 | 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 9 h, 12 h | ||||||
9 | Mouse | Athymic nude | Female | MTMSA-Trp | 5 mg/kg | 10 | 10 min, 30 min, 1 h, 3 h, 6 h | Destructive |
Plasma | Compound | Fraction Unbound (%) | ||
---|---|---|---|---|
1 µM | 3 µM | 10 µM | ||
Mouse 1 | MTM | 4.61 ± 0.63 | 1.95 ± 0.14 | 1.08 ± 0.35 |
MTMSA-Trp | <1 | <1 | <1 | |
Rat 2 | MTM | 17.99 ± 1.57 | 15.15 ± 2.85 | 16.82 ± 1.21 |
MTMSA-Trp | 2.41 ± 1.29 | 3.85 ± 0.08 | 3.88 ± 0.54 | |
Monkey 3 | MTM | 10.07 ± 1.34 | 12.75 ± 0.38 | 12.77 ± 1.19 |
MTMSA-Trp | 1.03 ± 0.27 | 1.02 ± 0.09 | 1.14 ± 0.15 | |
Human | MTM | 19.34 ± 1.57 | 18.28 ± 1.19 | 17.17 ± 0.70 |
MTMSA-Trp | <1 | <1 | <1 |
Species | Gender | Compound | Dose | AUC0–inf (ng/mL·h) | Extrapolated AUC0–inf (%) | CL (mL/h/kg) | Terminal t1/2 (h) | Vd (mL/kg) |
---|---|---|---|---|---|---|---|---|
Mouse | Male | MTM | 2 mg/kg | 1905 | 6.74 | 1050 | 2.72 | 4125 |
MTMSA-Trp | 2 mg/kg | 38,564 | 8.07 | 52 | 1.85 | 138 | ||
Rat | Male | MTM | 0.5 mg/kg | 175 | 53.52 | 2855 | 12.16 | 50,111 |
MTMSA-Trp | 0.5 mg/kg | 3486 | 1.43 | 143 | 1.56 | 324 | ||
Monkey | Male | MTM | 6.94 µg/kg | 92 | 15.32 | 75 | 3.27 | 354 |
MTMSA-Trp | 1.34 µg/kg | 139 | 5.77 | 10 | 0.37 | 5 | ||
MTM | 13.18 µg/kg | 254 | 17.88 | 52 | 3.49 | 262 | ||
MTMSA-Trp | 4.19 µg/kg | 181 | 4.99 | 23 | 0.78 | 26 |
Species | Gender | Compound | Dose | AUC0–inf (ng/mL·h) | Extrapolated AUC0–inf (%) | CL (mL/h/kg) | Terminal t1/2 (h) | Vd (mL/kg) |
---|---|---|---|---|---|---|---|---|
Mouse | Male | MTM | 69 µg/kg | 89 | 1.3 | 777 | 0.7 | 821 |
MTMSA-Trp | 69 µg/kg | 569 | 3.2 | 121 | 1.8 | 318 | ||
Rat | Male | MTM | 28 µg/kg | 46 | 3.1 | 608 | 0.8 | 713 |
MTMSA-Trp | 28 µg/kg | 223 | 8.4 | 126 | 2.4 | 428 |
Dose | AUC0–inf | Extrapolated AUC0–inf | CL | t1/2 | Vd |
---|---|---|---|---|---|
ng/mL·h | % | mL/h/kg | h | mL/kg | |
0.3 mg/kg | 4373 | 0.4 | 69 | 0.5 | 45 |
1 mg/kg | 24,419 | 0.2 | 41 | 1.3 | 75 |
3 mg/kg | 91,778 | 0.2 | 33 | 2.6 | 123 |
5 mg/kg | 13,7176 | 6.5 | 36 | 1.5 | 80 |
10 mg/kg | 216,281 | 5.6 | 46 | 1.2 | 81 |
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Niloy, K.K.; Horn, J.; Bhuiyan, N.H.; Shaaban, K.A.; Bhosale, S.S.; Prisinzano, T.E.; Thorson, J.S.; Rohr, J.; Leggas, M. Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog. Pharmaceutics 2025, 17, 765. https://doi.org/10.3390/pharmaceutics17060765
Niloy KK, Horn J, Bhuiyan NH, Shaaban KA, Bhosale SS, Prisinzano TE, Thorson JS, Rohr J, Leggas M. Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog. Pharmaceutics. 2025; 17(6):765. https://doi.org/10.3390/pharmaceutics17060765
Chicago/Turabian StyleNiloy, Kumar Kulldeep, Jamie Horn, Nazmul H. Bhuiyan, Khaled A. Shaaban, Suhas S. Bhosale, Thomas E. Prisinzano, Jon S. Thorson, Jurgen Rohr, and Markos Leggas. 2025. "Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog" Pharmaceutics 17, no. 6: 765. https://doi.org/10.3390/pharmaceutics17060765
APA StyleNiloy, K. K., Horn, J., Bhuiyan, N. H., Shaaban, K. A., Bhosale, S. S., Prisinzano, T. E., Thorson, J. S., Rohr, J., & Leggas, M. (2025). Preclinical Pharmacokinetic Evaluation of Mithramycin and Mithramycin SA Tryptophan-Conjugated Analog. Pharmaceutics, 17(6), 765. https://doi.org/10.3390/pharmaceutics17060765