Simultaneous Quantification and Pharmacokinetic Characterization of Doxapram and 2-Ketodoxapram in Porcine Plasma and Brain Tissue
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animal Study and Sample Generation
2.2. Reagents and Solvents
2.3. Preparation of Standard Solutions
2.4. Sample Preparation
2.5. Instrumental Analysis
2.6. Method Validation
2.7. Protein Binding
2.8. Calculations
3. Results and Discussion
3.1. Mass Spectrometry and Chromatography
3.2. Sample Preparation
3.3. Method Validation
3.4. Pharmacokinetics
3.5. Protein Binding
3.6. Brain-to-Plasma Ratio
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Study | Instruments | Range [ng/mL] | Analytes | Sample Matrix | Sample Volume | Run Time | Internal Standard | Sample Preparation |
---|---|---|---|---|---|---|---|---|
Aranda et al. (1988) [17] | HPLC-UV | 1000–15,000 | Doxapram, ketodoxapram, AHR 5904, AHR 0914 | Human serum | 50 µL | 15 min | Beta-hydroxy-phenyl-theophylline | LLE |
Barbé et al. (1999) [18] | HPLC-UV/VIS | 100–20,000 | Doxapram, ketodoxapram, AHR 5904, AHR 0914 | Human plasma | 60 µL | 10 min | Butobarbital | LLE |
Coutts et al. (1991) [19] | GC-N/P-D | - 1 | Doxapram and many metabolites | Human urine | 0.5–1 mL | - 2 | - | LLE |
Flint et al. (2018) [15] | UPLC-MS/MS | 50–4500 | Doxapram | Human plasma | 50 µL | 5 min | Fentanyl-d5 | PP |
50–5000 | Ketodoxapram | |||||||
Komatsu et al. (2005) [16] | GC-MS | 250–5000 | Doxapram | Human plasma | - 2 | - 2 | Diazepam | SPE |
LeGatt et al. (1986) [20] | GC-N/P-D | 100–10,000 | Doxapram and ketodoxapram | Human plasma | 200 µL | 6 min 3 | AHR-755 (doxapram analog) | LLE |
Lin et al. (2011) [21] | LC-MS/MS | 2–1000 | Doxapram | Rabbit plasma | 100 µL | 10 min | Urapidil | PP |
Nichol et al. (1980) [22] | GC-MS | -2 | Doxapram | Human blood, plasma | 50–100 µL | - 2 | Dextromoramide | LLE |
GC-FID | Human urine | 0.5–2 mL | ||||||
Ogawa et al. (2015) [23] | HPLC-UV/VIS | 30–? 4 | Doxapram | Human serum | 50 µL | 25 min 3 | Butobarbital | LLE |
10–? 4 | Ketodoxapram | |||||||
Robson and Prescott (1977) [24] | GC-N-D | 10–5000 | Doxapram | Human plasma | 2 mL | - 2 | Naftidrofuryl oxalte | LLE |
250–5000 | Ketodoxapram | |||||||
Roozekrans et al. (2017) [25] | LC-MS/MS | 2–5000 | Doxapram | Human plasma | - 2 | - 2 | - 2 | PP |
Sams et al. (1992) [26] | GC-N/P-D | 25–5000 | Doxapram | Horse plasma | 1 mL | - 2 | Diazepam | LLE |
Suzuki et al. (2017) [14] | LC-MS/MS | 20–5000 | Doxapram and ketodoxapram | Human serum | 25 µL | 17 min | Propranolol | PP |
Torok-Both et al. (1985) [27] | GC-N/P-D | - 2 | Doxapram | Human plasma | 20–100 µL | 8 min 3 | Diazepam | PP and LLE |
Human urine | 2–5 µL |
Animal | Cmax [ng/mL] | AUC [ng/mL*h] | VSS [L] | Cl [mL/min/kg] | t1/2 [h] | tmax [h] |
---|---|---|---|---|---|---|
Doxapram | ||||||
Pig 154 | 2149 | 1169 | 34.4 | 14.2 | 1.18 | - |
Pig 155 | 1490 | 986 | 51.5 | 16.9 | 1.26 | - |
Pig 156 | 1701 | 1403 | 37.1 | 11.9 | 1.69 | - |
Mean | 1780 ± 275 | 1186 ± 170 | 41.0 ± 7.5 | 14.3 ± 2.0 | 1.38 ± 0.22 | - |
2-Ketodoxapram | ||||||
Pig 154 | 31.2 | 157 | - | - | 2.47 | 0.33 |
Pig 155 | 26.2 | 139 | - | - | 2.36 | 1.00 |
Pig 156 | 39.5 | 185 | - | - | 2.42 | 0.75 |
Mean | 32.3 ± 5.5 | 160 ± 19 | - | - | 2.42 ± 0.04 | 0.69 ± 0.28 |
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Kraft, M.; Foerster, K.I.; Wiedmann, F.; Sauter, M.; Paasche, A.; Blochberger, P.L.; Yesilgöz, B.; L’hoste, Y.; Frey, N.; Haefeli, W.E.; et al. Simultaneous Quantification and Pharmacokinetic Characterization of Doxapram and 2-Ketodoxapram in Porcine Plasma and Brain Tissue. Pharmaceutics 2022, 14, 762. https://doi.org/10.3390/pharmaceutics14040762
Kraft M, Foerster KI, Wiedmann F, Sauter M, Paasche A, Blochberger PL, Yesilgöz B, L’hoste Y, Frey N, Haefeli WE, et al. Simultaneous Quantification and Pharmacokinetic Characterization of Doxapram and 2-Ketodoxapram in Porcine Plasma and Brain Tissue. Pharmaceutics. 2022; 14(4):762. https://doi.org/10.3390/pharmaceutics14040762
Chicago/Turabian StyleKraft, Manuel, Kathrin I. Foerster, Felix Wiedmann, Max Sauter, Amelie Paasche, Pablo L. Blochberger, Baran Yesilgöz, Yannick L’hoste, Norbert Frey, Walter E. Haefeli, and et al. 2022. "Simultaneous Quantification and Pharmacokinetic Characterization of Doxapram and 2-Ketodoxapram in Porcine Plasma and Brain Tissue" Pharmaceutics 14, no. 4: 762. https://doi.org/10.3390/pharmaceutics14040762
APA StyleKraft, M., Foerster, K. I., Wiedmann, F., Sauter, M., Paasche, A., Blochberger, P. L., Yesilgöz, B., L’hoste, Y., Frey, N., Haefeli, W. E., Burhenne, J., & Schmidt, C. (2022). Simultaneous Quantification and Pharmacokinetic Characterization of Doxapram and 2-Ketodoxapram in Porcine Plasma and Brain Tissue. Pharmaceutics, 14(4), 762. https://doi.org/10.3390/pharmaceutics14040762