Protein binding of prilocaine in human plasma: influence of concentration, pH and temperature

Bachmann, Bernd; Biscoping, J.; Sinning, E; Hempelmann, G.

doi:10.1111/j.1399-6576.1990.tb03093.x

Cited by 14 publications

(8 citation statements)

References 19 publications

(18 reference statements)

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“…17 The free fraction of prilocaine in plasma is about 55%. 18 Thus, in the present study unbound concentrations of prilocaine after cuff deflation were at the 0.1-0.3 mg ml À1 level.…”

Section: Discussionsupporting

confidence: 45%

Comparison of ropivacaine 2 mg ml −1 and prilocaine 5 mg ml −1 for i.v. regional anaesthesia in outpatient surgery

Niemi

Neuvonen

Rosenberg

2006

British Journal of Anaesthesia

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Compared with prilocaine 5 mg ml(-1), analgesia in IVRA with ropivacaine 2 mg ml(-1) developed slightly more slowly, while motor block developed at a similar rate. After the release of the tourniquet, sensation recovered quickly and at a similar rate in the two groups, except for a slightly slower recovery after ropivacaine in the innervation area of the median nerve, but no surgically useful extended analgesia after the cuff deflation was observed. Despite a 60% lower milligram-dose, ropivacaine plasma concentrations were markedly higher than those of prilocaine.

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“…17 The free fraction of prilocaine in plasma is about 55%. 18 Thus, in the present study unbound concentrations of prilocaine after cuff deflation were at the 0.1-0.3 mg ml À1 level.…”

Section: Discussionsupporting

confidence: 45%

Comparison of ropivacaine 2 mg ml −1 and prilocaine 5 mg ml −1 for i.v. regional anaesthesia in outpatient surgery

Niemi

Neuvonen

Rosenberg

2006

British Journal of Anaesthesia

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“…Principally, the study did not control for the influence on drug affinity of protein ionization. Studies correlating pH with the free fraction of prilocaine (Bachmann et al, 1990) and lidocaine (McNamara et al, 1981) had similar shortcomings.…”

Section: Downloaded Frommentioning

confidence: 99%

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein

Taheri

Cogswell²,

Gent³

et al. 2003

J Pharmacol Exp Ther

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Understanding the interaction of local anesthetics (LAs) with plasma proteins is essential to understanding their systemic pharmacology and toxicology. The molecular determinants of LA binding to the major variant (F1*S) of human ␣ 1 -acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using whole AGP and a novel, F1*S variant-selective probe previously developed in our laboratory. Equilibriumcompetitive displacement of this probe by LAs, observed by the recovery of AGP's fluorescence as the quenching probe was displaced from its high-affinity site, was characterized by inhibitory dissociation constants for the various LAs. The importance of electrostatic factors was assessed by examining the pH dependent binding of an ionizable LA, lidocaine, using the quaternary lidocaine derivative triethylammonium chloride] to control for pH dependent ionization of AGP. Uncharged lidocaine bound with at least 8 times the affinity of protonated lidocaine (K D ϭ 4.0 Ϯ 0.6 M and Ͼ32 M, respectively). This result is inconsistent with the current model of the AGP-binding site, which depicts a buried pocket having a negatively charged region that interacts with the amino termini of basic drugs. Consistent with the model, however, two sets of structurally homologous LAs (mepivacaine, ropivacaine, bupivacaine, and lidocaine, RAD-240, RAD-241, RAD-242, L-30, W-6603) demonstrated a strong positive correlation between hydrophobicity (measured as the octanol:buffer partition coefficient of the neutral species) and their free energies of dissociation. Given that the tertiary structure of AGP has proven refractory to resolution, these structure-activity studies should contribute to understanding the nature of the binding site on this important protein.Understanding the interaction of local anesthetics with plasma proteins is essential to predicting their systemic pharmacology and toxicology. Many basic drugs, including local anesthetics (LAs) and class I antiarrythmics, are bound in blood principally or in part by AGP (Routledge, 1986;Stanski and Watkins, 1986;Wood, 1986;Kremer et al., 1988). The binding of a drug to a plasma protein reduces its free fraction in serum, thus reducing its availability for active uptake or diffusion into surrounding tissue and significantly influencing its pharmacokinetics, toxicity, etc. (Wood, 1986).For example, the local anesthetic bupivacaine binds tightly to AGP (with K D ϭ 1 M) (Essassi et al., 1989), and this binding may mitigate the systemic toxicity of bupivacaine (Wulf et al., 1991;Mazoit et al., 1996).Indeed, altered pharmacokinetics have been observed following the binding of AGP to the LAs lidocaine and cocaine, and the same holds true with other clinically relevant amphipathic amines: amitriptyline, chlorpromazine, nicardipine, and verapamil (Benet and Hoener, 2002). For example, AGP concentration has been shown to correlate inversely with the free fraction of the LA ropivacaine 60 min after epidural injection (Porter et al., 2001). Also, one of the AGP variants...

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“…Methämoglobin: Die maximalen Met-Hb-Spiegel betrugen 0, 3 Obwohl sie meistens klinisch ohne Bedeutung bleibt, kann die dramatische Zyanose die Patienten und das Personal beunruhigen. Von Methämoglobinämie spricht man, wenn mehr als 1% des Hämoglobineisens in oxidierter Form vorliegt.…”

Section: Pharmacokinetics Of Tumescent Local Anaesthesia With Prilocaunclassified

Pharmakokinetische Untersuchungen bei der Tumeszenz-Lokalanästhesie mit Prilocain in der Varizenchirurgie

Sagoo¹,

Inoue²,

Winker³

et al. 2000

Phlebologie

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ZusammenfassungTumeszenz-Lokalanästhesie (TLA) mit Prilocain gewährleistet eine ausgezeichnete Analgesie in der Varizenchirurgie ohne die Nachteile der Vollnarkose und Spinalanästhesie. Bei TLA werden große Volumina einer stark verdünnten (0,09%igen) Tumeszenzlösung, bestehend aus 1000 mg Prilocain, 1,0 mg Adrenalin und 10 mEq Natriumbikarbonat in 1000 ml physiologischer Kochsalzlösung subkutan entlang der zu operierenden Venen infiltriert. Ziel: Die Studie hatte den Zweck, die zeitlichen Verlaufskurven der Plasma-Prilocainkonzentration (PPC) und Methämoglobin (Met-Hb)-Werte nach TLA mit Prilocain in bestimmten Intervallen über 24 Stunden zu ermitteln. Methode: Untersucht wurden 3 Gruppen von je 8 Patienten (n = 24) mit 10, 15 bzw. 20 mg/kg Prilocain als TLA. Ergebnis: Die entsprechenden Spitzenwerte der mittleren PPC wurden 7 bis 9 Stunden nach TLA erreicht und betrugen 0,47, 0,51 bzw. 0,71 _g/ml. Erste zentral neurotoxische Symptome können bei einer PPC von 5 _g/ml auftreten. Die kritische Krampfschwellenkonzentration beträgt 10-12 _g/ml. Bei Lokalanästhesie in konventioneller Technik werden mehrfach höhere Spitzen-Plasmaspiegel des Anästhetikums innerhalb der ersten Stunde erreicht. Bei 5 Patienten wurde simultan Met-Hb bestimmt. Methämoglobinämie ist eine potentielle Komplikation von höheren Prilocain- Dosierungen. Maximale Met-Hb-Werte von 0,3 bis 11,0% des Gesamt-Hb wurden durchschnittlich 14 Stunden nach TLA gemessen. Zyanose entsteht bei Met-Hb-Werten von 15% des Gesamt-Hb. Bei keinem Patienten traten klinische Komplikationen auf. Schlußfolgerungen: TLA mit Prilocain in Dosierungen bis zu 20 mg/kg verursacht sehr niedrige maximale PPC und Met-Hb- Konzentrationen, die weit unter den kritischen toxischen Grenzen liegen. Aufgrund dieser Ergebnisse kann die TLA unter klinischen, pharmakokinetischen und damit forensischen Gesichtspunkten als ein sicheres und unbedenkliches Anästhesieverfahren in der Varizenchirurgie angesehen werden.

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Protein binding of prilocaine in human plasma: influence of concentration, pH and temperature

Cited by 14 publications

References 19 publications

Comparison of ropivacaine 2 mg ml −1 and prilocaine 5 mg ml −1 for i.v. regional anaesthesia in outpatient surgery

Comparison of ropivacaine 2 mg ml −1 and prilocaine 5 mg ml −1 for i.v. regional anaesthesia in outpatient surgery

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein

Pharmakokinetische Untersuchungen bei der Tumeszenz-Lokalanästhesie mit Prilocain in der Varizenchirurgie

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Protein binding of prilocaine in human plasma: influence of concentration, pH and temperature

Cited by 14 publications

References 19 publications

Comparison of ropivacaine 2 mg ml −1 and prilocaine 5 mg ml −1 for i.v. regional anaesthesia in outpatient surgery

Comparison of ropivacaine 2 mg ml −1 and prilocaine 5 mg ml −1 for i.v. regional anaesthesia in outpatient surgery

Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α1-Acid Glycoprotein

Pharmakokinetische Untersuchungen bei der Tumeszenz-Lokalanästhesie mit Prilocain in der Varizenchirurgie

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Hydrophobic and Ionic Factors in the Binding of Local Anesthetics to the Major Variant of Human α₁-Acid Glycoprotein