Pharmacokinetics of Succinylcholine in Man.

Hoshi, Kunihiko; Hashimoto, Yuichi; Matsukawa, Shu

doi:10.1620/tjem.170.245

Cited by 14 publications

(12 citation statements)

References 10 publications

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“…Also, data from the user-defined approach (submodel 1) were supportive of an extremely fast SUX degradation (data not shown). All existing publications dealing with the in vivo kinetics of SUX corroborate these, in part empirical, observations (1,5,7,22).…”

Section: Discussionsupporting

confidence: 67%

Pharmacokinetic Properties of Succinylmonocholine in Surgical Patients

Kuepper

Mußhoff

Hilger

et al. 2011

Journal of Analytical Toxicology

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Intoxications with succinylcholine (SUX) lead to a potentially lethal respiratory paralysis, and forensic cases involving accidental or deliberate SUX-application have been reported. Detection of SUX as well as its metabolite succinylmonocholine (SMC) is difficult: both substances are analytically challenging, and the extremely short plasma half-life of SUX additionally hampers detection of the parent compound. Pharmacokinetic data are scarce on SUX and non-existent on SMC. To enhance forensic knowledge concerning SUX intoxications, plasma pharmacokinetics of SMC were investigated in anesthetized patients. Fifteen subjects scheduled for a surgical procedure were included in this study. Muscle-relaxation was initialized with a bolus injection of 80-100 mg SUX. Blood sampling was performed within 6 h after SUX application using paraoxonized tubes. Collected plasma was processed according to a validated isotope dilution high-performance liquid chromatography-tandem mass spectrometry method using ion-pair solid-phase extraction. Pharmacokinetic parameters were derived from a user-defined as well as a three-compartment model. For SMC, peak plasma concentrations were reached after 0.03-2.0 min. In contrast to SUX, SMC was more slowly and more extensively distributed, featuring triphasic plasma concentration time profiles. Pharmacokinetic key parameters were subject to interindividual variation of potential forensic importance, with terminal half-lives of 1-3 h indicating a detection interval of 8-24 h for SMC in plasma. SMC was proven to be the only realistic SUX marker in a forensic context. The present work defines meaningful detection windows for plasmatic SMC after SUX application and offers guideline values for forensic toxicological casework. IntroductionSuccinylcholine (SUX) is a bis-quaternary ammonium compound that, because of its structural resemblance yet prolonged biological activity compared to acetylcholine (delayed degradation by the acetylcholinesterase EC 3.1.1.7), acts as a depolarizing muscle relaxant. The drug is routinely used in anesthesia, during which the resulting respiratory paralysis is compensated for by artificial ventilation, but it also has the reputation of being an undetectable poison: whenever respiratory assistance is not provided, a therapeutic dose of SUX can cause lethal apnea, with the drug being degraded within minutes (1-7) by unspecific cholinesterases (butyrylesterase; EC 3.1.1.8). The primary degradation product is succinylmonocholine (SMC), which is further metabolized into the endogenous substances succinate and choline (Figure 1). The fact that both SUX and SMC are analytically challenging compounds critically hampers forensic investigation. Additionally, the recent report on detection of the more stable SMC in SUX- Pharmacokinetic Properties of Succinylmonocholine in Surgical Patients

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Section: Discussionsupporting

confidence: 67%

Pharmacokinetic Properties of Succinylmonocholine in Surgical Patients

Kuepper

Mußhoff

Hilger

et al. 2011

Journal of Analytical Toxicology

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“…Even though this drug has been widely used since 1951 as a muscle relaxant for surgery, only one human pharmacokinetic study has been reported and it had a sensitivity of 2000 ng/ml (1). The monitoring of the in vivo disposition of SUX would provide valuable information about the doseeffect relationship.…”

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confidence: 99%

Measurement of Succinylcholine Concentration in Human Plasma by Electrospray Tandem Mass Spectrometry

Roy

Boismenu

Gao

et al. 2001

Analytical Biochemistry

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“…Within the framework of a two-compartment model [10], an extensive distribution of SUX has been reported, and may be seen as a contributing-if not the most dominantfactor influencing the initial decrease in plasma concentration of this substance [4,5,20]. The extent of SUX distribution, however, is hard to define, as analyte degradation in the central compartment (and most probably in the periphery as well) is likely to cause an underestimation of its true distribution volume [10].…”

Section: Discussionmentioning

confidence: 99%

“…The extent of SUX distribution, however, is hard to define, as analyte degradation in the central compartment (and most probably in the periphery as well) is likely to cause an underestimation of its true distribution volume [10]. As a result thereof, but also depending on the applied kinetic model, extremely divergent steady state distribution volumes of SUX, i.e., 2.2 [4], 16.4 [20], and 39 ml/kg [10] were reported. Again, it has to be kept in mind that older studies may not accurately represent the conditions in vivo, which is why the work of Roy et al [10], being able to at least prove a dispersion of SUX in the entire intravascular space, seems most plausible.…”

Section: Discussionmentioning

confidence: 99%

Degradation and elimination of succinylcholine and succinylmonocholine and definition of their respective detection windows in blood and urine for forensic purposes

et al. 2011

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The muscle relaxant succinylcholine (SUX) evokes respiratory paralysis, and numerous cases of fatal SUX intoxication have been reported. Detection of SUX and its metabolite succinylmonocholine (SMC) is difficult, both due to their (bis-) quaternary structure and the extreme hydrolytic susceptibility of SUX, and data on degradation kinetics of SUX and SMC is scarce. The present study investigates the in vivo and in vitro degradation as well as elimination of both target analytes using authentic blood and urine samples from anesthetized patients. With a special focus on the urinary data and stabilization issues, this work intends to considerably enhance the forensic knowledge concerning SUX intoxications and to present the reader with practical analytical strategies to cope with such difficult cases. Eighteen subjects undergoing surgery and requiring arterial as well as bladder catheters were included in this study. Muscle relaxation was initialized with a bolus injection of 80-100 mg SUX. Blood and urine samples were either collected using paraoxonized (n = 15) or non-modified (n = 3) tubes. Sampling was performed within 6 h after SUX application following a pre-assigned schedule. Samples were processed according to a validated isotope dilution HPLC-MS/MS method using ion-pair solid-phase extraction. In blood, SUX was usually detectable for up to 10 min post-injection, while detection of SMC was possible over the whole observation period of 6 h. Effectiveness of organophosphate stabilization was proven for both analytes and is therefore recommended. In freshly secreted urine, detection windows of a minimum of 2 h as opposed to 6 h have been determined for SUX versus SMC, respectively. Considering SMC plasma kinetics, detection of the metabolite in blood and freshly secreted urine appears to be possible over a period of at least 8-24 h. Paraoxon did not enhance the stability of either target substance in urine, stabilization of urine samples is nonetheless recommended. In summary, SMC was proven to be the most promising target analyte in SUX analysis, with urine being the proposed matrix of choice for forensic applications. Furthermore, our work defines meaningful detection windows for SUX and SMC in blood and urine as routine matrices and presents sampling recommendations as well as guideline values for forensic toxicological analysis.

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Pharmacokinetics of Succinylcholine in Man.

Cited by 14 publications

References 10 publications

Pharmacokinetic Properties of Succinylmonocholine in Surgical Patients

Pharmacokinetic Properties of Succinylmonocholine in Surgical Patients

Measurement of Succinylcholine Concentration in Human Plasma by Electrospray Tandem Mass Spectrometry

Degradation and elimination of succinylcholine and succinylmonocholine and definition of their respective detection windows in blood and urine for forensic purposes

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