Adding epinephrine to lidocaine solutions increases the intensity and duration of sciatic nerve block in the rat. The early increase in intensity is not matched with an increase in intraneural lidocaine content at these early times, although the prolonged duration of block by epinephrine appears to correspond to an enlarged lidocaine content in nerve at later times, as if a very slowly emptying "effector compartment" received a larger share of the dose. The increase in early analgesia without increased lidocaine content may be explained by a pharmacodynamic action of epinephrine that transiently enhances lidocaine's potency, but also by a pharmacokinetic effect that alters the distribution of the same net content of lidocaine within the nerve.

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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