title: Biphasic drug absorption from the epidural space of the dog may limit the utility of a slow release medium molecular weight hyaluronic acid-lidocaine ionic complex formulation.
abstract: Previous epidural studies conducted in rabbits have described a viscous lidocaine-hyaluronate formulation (L-HA) that prolonged the duration of sensory blockade twofold and decreased the rate of drug absorption fourfold relative to a solution formulation. As further evaluation of the L-HA formulation required studies in a larger animal that more closely reflected the characteristic absorption kinetics observed in humans, a conscious dog model was used to functionally and kinetically evaluate the viscous formulation relative to lidocaine solution. In terms of the measured pharmacodynamic end point (loss of weight-bearing ability in hind legs), epidural administration of the L-HA formulation did not prolong the duration of action relative to lidocaine solution in spite of a markedly altered pharmacokinetic profile. For example, administration of L-HA reduced the mean plasma lidocaine Cmax value approximately 50% and increased the Tmax value approximately fivefold relative to lidocaine solution. However, the viscous L-HA formulation did cause a significant prolongation in the latency of onset (P < 0.001) relative to lidocaine solution. The dog exhibited "flip-flop" pharmacokinetics and absorption was biphasic after epidural administration of lidocaine solution (apparent t1/2 of the fast and slow absorption phases were 4 min and 131 min, respectively). The L-HA formulation markedly altered the absorption kinetics such that a single, slow absorption phase was evident (apparent t1/2 of 56 min), although this rate was more rapid than the slow phase observed after lidocaine solution. It is possible that the inability of the hyaluronate-based formulation to further reduce the magnitude of the slow absorption phase resulted in the failure to prolong the duration of action. These data highlight the need to carefully consider the absorption kinetics and pharmacokinetic characteristics of the animal models chosen to evaluate new formulation of epidurally administered local anesthetics.
authors.affiliation: Department of Pharmaceutics, Victorian College of Pharmacy, Monash University, Parkville, Australia.
authors.forename: M M
authors.initials: MM
authors.lastname: Doherty
authors.forename: P J
authors.initials: PJ
authors.lastname: Hughes
authors.forename: S A
authors.initials: SA
authors.lastname: Charman
authors.forename: K V
authors.initials: KV
authors.lastname: Brock
authors.forename: N V
authors.initials: NV
authors.lastname: Korszniak
authors.forename: W N
authors.initials: WN
authors.lastname: Charman
mesh_terms: D000042:Absorption; D000767:Anesthesia, Epidural; D000771:Anesthesia, Intravenous; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004285:Dogs; D004338:Drug Combinations; D004347:Drug Interactions; D004824:Epidural Space / Q000378:metabolism; D005260:Female; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D008012:Lidocaine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D008970:Molecular Weight; D009407:Nerve Block; D011897:Random Allocation; D013997:Time Factors; D016474:Weight-Bearing
chemical_list: D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D006820:Hyaluronic Acid; D008012:Lidocaine