Evaluation of Lipid Emulsion-Mediated Sequestration and Redistribution of the Highly Lipophilic Carbamazepine in the Plasma of Rats
Abstract
Aim: The idea that intravenous lipid emulsion (ILE) may serve as a "reservoir" for lipophilic drugs has emerged in research as an intravascular "lipid sink" effect. Carbamazepine (CBZ) is a widely used anticonvulsant. This compound has a neutral and highly lipophilic structure and can easily cross body membranes. In this study, our hypothesis focused on the potential efficacy of ILE in modulating blood carbamazepine concentrations.
Material and Methods: 22 adult Sprague-Dawley rats were divided into four groups. All groups received CBZ at a dose of 20 mg/kg orogastrically. The first group was the control group. In the second group (activated charcoal group), activated charcoal (AC) was administered orogastrically at a dose of 1 g/kg five minutes after orogastric administration of carbamazepine. The third group (lipid group) received ILE at a dose of 3 ml/kg/min at the fifth minute. The fourth group was the saline group, in which 16 ml/kg of 0.9% NaCl was infused at the fifth minute. Blood samples of 0.5 ml were collected at 0, 4, 8, and 24 hours. Plasma was separated by centrifugation (4000 rpm, 10 minutes) and stored at -80oC for determination of CBZ concentrations. An Agilent 6410B HP-1200 LC series (USA) liquid chromatography system was used for analysis. Quantitative analysis was performed in the multiple reaction mode with electrospray positive ionization (ES+).
Results: At the 8th hour of orogastric CBZ administration, CBZ concentration was significantly lower in the activated charcoal group than in the lipid and saline groups (p: 0.021; p: 0.023; p<0.05, respectively). There was no significant difference in CBZ concentrations between the other groups at 8 hours (p>0.05). In the lipid group, the increase in CBZ plasma concentrations was statistically significant at 4 and 8 hours compared to 0 hours (p: 0.005; p: 0.005, respectively).
Conclusion: In the lipid group, plasma CBZ concentrations increased at 4 and 8 hours in plasma samples from which lipids were separated by differential centrifugation. In the lipid group, no effects favoring drug-lipid sequestration on the plasma distribution of CBZ were observed.
Ethical Statement
The study (decision number: 634, approval date: 22.12.2017) was initiated following the approval of the Ethics Committee of the Local Ethics Committee for Animal Experiments at Yeditepe University. The research was conducted at the Laboratory for Experimental Animal Research at the Faculty of Medicine, Yeditepe University, Istanbul, Turkey. The study followed all relevant international, national, and institutional guidelines for the appropriate care and use of animals in research.
Project Number
634
Thanks
We are deeply grateful to all those who have contributed to the success of this project. We would like to thank Ahmet Aydın PhD for his invaluable input and support throughout the research process. Their insights and expertise were instrumental in shaping the direction of this project.
References
- Breton H, Cociglio M, Bressolle F, Peyriere H, Blayac JP, Hillaire-Buys D. Liquid chromatography-electrospray mass spectrometry determination of carbamazepine, oxcarbazepine and eight of their metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;828(1-2):80-90. doi:10.1016/j.jchromb.2005.09.019
- Zita L, Kurhan S, Krunt O, Chmelíková E, Kraus A, Čítek J, Klouček P, Stupka R. The Effect of Carbamazepine on Performance, Carcass Value, Hematological and Biochemical Blood Parameters, and Detection of Carbamazepine and Its Metabolites in Tissues, Internal Organs, and Body Fluids in Growing Rabbits. Animals (Basel). 2023 Jun 20;13(12):2041. doi: 10.3390/ani13122041. PMID: 37370551; PMCID: PMC10295208.
- Ghannoum M, Yates C, Galvao TF, et al. Extracorporeal treatment for carbamazepine poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila). 2014;52(10):993-1004. doi:10.3109/15563650.2014.973572
- Bertilsson L. Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet. 1978;3(2):128-143. doi:10.2165/00003088 197803020-00003
- Vree TB, Janssen TJ, Hekster YA, et al. Clinical pharmacokinetics of carbamazepine and its epoxy and hydroxy metabolites in humans after an overdose. Ther Drug Monit. 1986;8(3):297-304. doi:10.1097/00007691-198609000-00011
- Chyka PA, Seger D, Krenzelok EP, Vale JA; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43(2):61-87. doi:10.1081/clt-200051867
- Krieglstein J, Meffert A, Niemeyer DH. Influence of emulsified fat on chlorpromazine availability in rabbit blood. Experientia. 1974;30(8):924-926. doi:10.1007/BF01938365
- Weinberg G, Lin B, Zheng S, et al. Partitioning effect in lipid resuscitation: further evidence for the lipid sink. Crit Care Med. 2010;38(11):2268-2269. doi:10.1097/CCM.0b013e3181f17d85
- Weinberg GL, VadeBoncouer T, Ramaraju GA, et al. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology. 1998;88(4):1071-1075. doi:10.1097/00000542-199804000-00028
- Jaffal K, Chevillard L, Mégarbane B. Lipid Emulsion to Treat Acute Poisonings: Mechanisms of Action, Indications, and Controversies. Pharmaceutics. 2023 10.3390/pharmaceutics15051396. May PMID: (5):1396. 37242638; doi: PMCID: PMC10224337.
- Kuo I, Akpa BS. Validity of the lipid sink as a mechanism for the reversal of local anesthetic systemic toxicity: a physiologically based pharmacokinetic model study. Anesthesiology. 2013;118(6):1350-1361. doi:10.1097/ALN.0b013e31828ce74d
- Uzunget SC, Evrin T, Uzunget SB, et al. Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity. Am J Emerg Med. 2018;36(8):1346-1349. doi:10.1016/j.ajem.2017.12.039
- Turan CA, Ozturk TC, Akoglu EU, et al. The Role of Intralipid Emulsion in the Rat Model of Digoxin Intoxication. Cardiovasc Toxicol. 2018;18(4):329-336. doi:10.1007/s12012-018-9444-4
- Hurley, W. T., and P. Hanlon. "Lipid emulsion as an antidote at the Washington Poison Center; use in carbamazepine, flecanide, hydroxychloroquine, bupivacaine, and bupropion." Clinical Toxicology. Vol. 47. No. 7. 52 Vanderbilt Ave, New York, NY 10017 USA: Informa Healthcare, 2009.
- Niiya T, Litonius E, Petäjä L, Neuvonen PJ, Rosenberg PH. Intravenous lipid emulsion sequesters amiodarone in plasma and eliminates its hypotensive action in pigs. Ann Emerg Med. 2010;56(4):402-408.e2. doi:10.1016/j.annemergmed.2010.06.001
- Litonius E, Niiya T, Neuvonen PJ, Rosenberg PH. No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication despite significant entrapment of amitriptyline. Basic Clin Pharmacol Toxicol. 2012;110(4):378-383. doi:10.1111/j.1742-7843.2011.00826.x
- Harvey M, Cave G, Hoggett K. Correlation of plasma and peritoneal diasylate clomipramine concentration with hemodynamic recovery after intralipid infusion in rabbits. Acad Emerg Med. 2009;16(2):151 156. doi:10.1111/j.1553-2712.2008.00313.x
- Brahmi N, Kouraichi N, Thabet H, Amamou M. Influence of activated charcoal on the pharmacokinetics and the clinical features of carbamazepine poisoning. Am J Emerg Med. 2006;24(4):440-443. doi:10.1016/j.ajem.2005.12.025
- Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1999;37(6):731-751. doi:10.1081/clt-100102451
Yüksek Lipofilik Karbamazepinin Sıçan Plazmasında Lipid Emülsiyonu Aracılı Sekestrasyonu ve Yeniden Dağılımının Değerlendirilmesi
Abstract
Amaç: İntravenöz lipid emülsiyonunun (ILE) lipofilik ilaçlar için bir "rezervuar" görevi görebileceği fikri, intravasküler "lipid sink" etkisi olarak araştırmalarda ortaya çıkmıştır. Karbamazepin (CBZ) yaygın olarak kullanılan bir antikonvülzandır. Bu bileşik nötral ve oldukça lipofilik bir yapıya sahiptir ve vücut membranlarını kolayca geçebilir. Bu çalışmada hipotezimiz, ILE'nin kan karbamazepin konsantrasyonlarını modüle etmedeki potansiyel etkinliğine odaklanmıştır.
Gereç ve Yöntemler: 22 yetişkin Sprague-Dawley sıçan dört gruba ayrıldı. Tüm gruplara 20 mg/kg dozunda CBZ orogastrik olarak verildi. Birinci grup kontrol grubuydu. İkinci grupta (aktif kömür grubu), karbamazepinin orogastrik uygulamasından beş dakika sonra aktif kömür (AC) 1 g/kg dozunda orogastrik olarak uygulandı. Üçüncü gruba (lipid grubu) beşinci dakikada 3 ml/kg/dk dozunda ILE verildi. Dördüncü grup, beşinci dakikada 16 ml/kg %0,9 NaCl infüze edilen salin grubuydu. 0, 4, 8 ve 24. saatlerde 0,5 ml kan örnekleri toplandı. Plazma santrifüj (4000 rpm, 10 dakika) ile ayrıldı ve CBZ konsantrasyonlarının belirlenmesi için -80oC'de saklandı. Analiz için bir Agilent 6410B HP-1200 LC serisi (ABD) sıvı kromatografi sistemi kullanıldı. Kantitatif analiz elektrosprey pozitif iyonizasyon (ES+) ile çoklu reaksiyon modunda gerçekleştirildi.
Bulgular: Orogastrik CBZ uygulamasının 8. saatinde, CBZ konsantrasyonu aktif kömür grubunda lipid ve salin gruplarına göre anlamlı derecede düşüktü (sırasıyla p: 0.021; p: 0.023; p<0.05). Diğer gruplar arasında 8. saatte CBZ konsantrasyonları açısından anlamlı bir fark bulunmadı (p>0.05). Lipid grubunda, CBZ plazma konsantrasyonlarındaki artış başlangıca kıyasla 4 ve 8. saatlerde istatistiksel olarak anlamlıydı (sırasıyla p: 0.005; p: 0.005).
Sonuç: Lipid grubunda, lipidlerin diferansiyel santrifüjleme ile ayrıldığı plazma örneklerinde plazma CBZ konsantrasyonları 4 ve 8. saatlerde artmıştır. Lipid grubunda, CBZ'nin plazma dağılımı üzerinde ilaç-lipid sekestrasyonunu destekleyen herhangi bir etki gözlenmedi.
Project Number
634
References
- Breton H, Cociglio M, Bressolle F, Peyriere H, Blayac JP, Hillaire-Buys D. Liquid chromatography-electrospray mass spectrometry determination of carbamazepine, oxcarbazepine and eight of their metabolites in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;828(1-2):80-90. doi:10.1016/j.jchromb.2005.09.019
- Zita L, Kurhan S, Krunt O, Chmelíková E, Kraus A, Čítek J, Klouček P, Stupka R. The Effect of Carbamazepine on Performance, Carcass Value, Hematological and Biochemical Blood Parameters, and Detection of Carbamazepine and Its Metabolites in Tissues, Internal Organs, and Body Fluids in Growing Rabbits. Animals (Basel). 2023 Jun 20;13(12):2041. doi: 10.3390/ani13122041. PMID: 37370551; PMCID: PMC10295208.
- Ghannoum M, Yates C, Galvao TF, et al. Extracorporeal treatment for carbamazepine poisoning: systematic review and recommendations from the EXTRIP workgroup. Clin Toxicol (Phila). 2014;52(10):993-1004. doi:10.3109/15563650.2014.973572
- Bertilsson L. Clinical pharmacokinetics of carbamazepine. Clin Pharmacokinet. 1978;3(2):128-143. doi:10.2165/00003088 197803020-00003
- Vree TB, Janssen TJ, Hekster YA, et al. Clinical pharmacokinetics of carbamazepine and its epoxy and hydroxy metabolites in humans after an overdose. Ther Drug Monit. 1986;8(3):297-304. doi:10.1097/00007691-198609000-00011
- Chyka PA, Seger D, Krenzelok EP, Vale JA; American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol (Phila). 2005;43(2):61-87. doi:10.1081/clt-200051867
- Krieglstein J, Meffert A, Niemeyer DH. Influence of emulsified fat on chlorpromazine availability in rabbit blood. Experientia. 1974;30(8):924-926. doi:10.1007/BF01938365
- Weinberg G, Lin B, Zheng S, et al. Partitioning effect in lipid resuscitation: further evidence for the lipid sink. Crit Care Med. 2010;38(11):2268-2269. doi:10.1097/CCM.0b013e3181f17d85
- Weinberg GL, VadeBoncouer T, Ramaraju GA, et al. Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology. 1998;88(4):1071-1075. doi:10.1097/00000542-199804000-00028
- Jaffal K, Chevillard L, Mégarbane B. Lipid Emulsion to Treat Acute Poisonings: Mechanisms of Action, Indications, and Controversies. Pharmaceutics. 2023 10.3390/pharmaceutics15051396. May PMID: (5):1396. 37242638; doi: PMCID: PMC10224337.
- Kuo I, Akpa BS. Validity of the lipid sink as a mechanism for the reversal of local anesthetic systemic toxicity: a physiologically based pharmacokinetic model study. Anesthesiology. 2013;118(6):1350-1361. doi:10.1097/ALN.0b013e31828ce74d
- Uzunget SC, Evrin T, Uzunget SB, et al. Evaluation of activated charcoal and lipid emulsion treatment in model of acute rivaroxaban toxicity. Am J Emerg Med. 2018;36(8):1346-1349. doi:10.1016/j.ajem.2017.12.039
- Turan CA, Ozturk TC, Akoglu EU, et al. The Role of Intralipid Emulsion in the Rat Model of Digoxin Intoxication. Cardiovasc Toxicol. 2018;18(4):329-336. doi:10.1007/s12012-018-9444-4
- Hurley, W. T., and P. Hanlon. "Lipid emulsion as an antidote at the Washington Poison Center; use in carbamazepine, flecanide, hydroxychloroquine, bupivacaine, and bupropion." Clinical Toxicology. Vol. 47. No. 7. 52 Vanderbilt Ave, New York, NY 10017 USA: Informa Healthcare, 2009.
- Niiya T, Litonius E, Petäjä L, Neuvonen PJ, Rosenberg PH. Intravenous lipid emulsion sequesters amiodarone in plasma and eliminates its hypotensive action in pigs. Ann Emerg Med. 2010;56(4):402-408.e2. doi:10.1016/j.annemergmed.2010.06.001
- Litonius E, Niiya T, Neuvonen PJ, Rosenberg PH. No antidotal effect of intravenous lipid emulsion in experimental amitriptyline intoxication despite significant entrapment of amitriptyline. Basic Clin Pharmacol Toxicol. 2012;110(4):378-383. doi:10.1111/j.1742-7843.2011.00826.x
- Harvey M, Cave G, Hoggett K. Correlation of plasma and peritoneal diasylate clomipramine concentration with hemodynamic recovery after intralipid infusion in rabbits. Acad Emerg Med. 2009;16(2):151 156. doi:10.1111/j.1553-2712.2008.00313.x
- Brahmi N, Kouraichi N, Thabet H, Amamou M. Influence of activated charcoal on the pharmacokinetics and the clinical features of carbamazepine poisoning. Am J Emerg Med. 2006;24(4):440-443. doi:10.1016/j.ajem.2005.12.025
- Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol. 1999;37(6):731-751. doi:10.1081/clt-100102451
Details
| Primary Language | English |
|---|---|
| Subjects | Emergency Medicine |
| Journal Section | Original Articles |
| Authors | |
| Project Number | 634 |
| Early Pub Date | April 3, 2024 |
| Publication Date | March 31, 2024 |
| Published in Issue | Year 2024 Volume: 7 Issue: 1 |
