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Orosomucoid polymorphisms influence plasma drug binding in humans; however, canine variants and their effect on drug plasma protein binding have not yet been reported. In this study, the orosomucoid gene (ORM1) was sequenced in 100 dogs to identify the most common variant and its allele frequency determined in 1,464 dogs (from 64 breeds and mixed-breed dogs). Plasma protein binding extent of amitriptyline, indinavir, verapamil, and lidocaine were evaluated by equilibrium dialysis using plasma from ORM1 genotyped dogs (n = 12). Free and total drug plasma concentrations were quantified by liquid chromatography-mass spectrometry. From the five polymorphisms identified in canine ORM1, two were nonsynonymous. The most common was c.70G>A (p.Ala24Thr) with an allele frequency of 11.2% (n = 1464). Variant allele frequencies varied by breed, reaching 74% in Shetland Sheepdogs (n = 21). Free drug fractions did not differ significantly (p > .05; Mann-Whitney U) between plasma collected from dogs with c.70AA (n = 4) and those with c.70GG (n = 8) genotypes. While c.70G>A did not affect the extent of plasma protein binding in our study, the potential biological and pharmacological implication of this newly discovered ORM1 variant in dogs should be further investigated., (© 2020 John Wiley & Sons Ltd.)

Intravenous (iv), subcutaneous (sq), and topical (tp) lidocaine was administered to six horses in a cross-over, randomized design study. Samples were collected for up to 72 hr. Compartmental models were used to investigate the pharmacokinetics of (LD) and its metabolites 3-hydroxylidocaine (3-OH), 4-hydroxylidocaine (4-OH), and monoethylglycinexylidide (MEGX). Metabolites 3-OH and 4-OH were present in conjugated forms, whereas LD and metabolite MEXG were present primarily in the un-conjugated form. Plasma concentrations of LD after iv administration (100 mg) were described by three-compartment model with an additional three compartments to describe the elimination of metabolites. Median (range) elimination micro-constants (K e ) for LD, 3-OH, 4-OH, and MEXG were 4.12 (2.62-6.23), 1.25 (1.10-2.15), 1.79 (1.22-2.39), and 1.69 (1.03-1.99)/hr, respectively. Median (range) values of alpha (t ½α ), beta (t ½β ), and gamma (t ½γ ) half-lives were 0.08 (0.07-0.13), 0.57 (0.15-1.25), and 4.11 (0.52-7.36) hr. Plasma concentrations of LD after sq (200 mg) administration were described by absorption and two-compartment elimination model. The median (range) of the LD absorption half-life (t ½ab ) was 0.47 (0.29-0.61) hr. The K e for LD, 3-OH, 4-OH, and MEXG was 3.91 (1.48-9.25), 1.00 (0.78-1.08), 1.76 (0.96-2.11), and 1.13 (0.69-1.33)/hr. The median (range) of t ½α and t ½β was 0.15 (0.06-0.27) and 3.04 (2.53-6.39) hr. Plasma concentrations of LD after tp (400 mg) application were described by one-compartment model with a t ½ab of 8.49 (5.16-11.80) hr. The K e for LD, 3-OH, and MEXG was 0.24 (0.10-0.81), 0.41 (0.08-0.93), and 0.38 (0.26-1.14)/hr., (© 2018 John Wiley & Sons Ltd.)

Objectives: To compare, via CT imaging, the spread of different volumes of diluted iodinated contrast medium in the transversus abdominis muscle plane of dog cadavers., Methods: Prospective, randomised study. An electro stimulation or a SonoTAP needle was inserted in plane with the ultrasound beam in the fascia between the internal oblique and transversus abdominis muscles. A test dose of 1 ml of diluted contrast (30 mg/mL iohexol) was injected to confirm positioning, followed by 0 · 5 mL/kg (n=14) or 1 mL/kg (n=12) and the distribution of the fluid compared., Results: Contrast medium was identified exclusively in the transversus abdominis plane in 19 of 26 dogs. In one dog, the contrast lay between the external and internal oblique muscles and partially in three dogs. Intraperitoneal contrast was detected in 6 of 26 dogs (23%). No significant differences were found in the dorso-ventral or cranio-caudal spread or area of distribution but a significant difference was found in the transverse spread. There was an association between poor ultrasound visualisation of the tip of the needle and intraperitoneal injection., Clinical Significance: Injection of 1 mL/kg of diluted contrast did not result in wider cranio-caudal spread in the transversus abdominis muscle plane of dog cadavers when compared with 0 · 5 mL/kg. Intraperitoneal injection is a risk and might be reduced with good needle visualisation., (© 2017 British Small Animal Veterinary Association.)

The objective was to compare plasma lidocaine concentrations when a commercially available 5% lidocaine patch was placed on intact skin vs. an incision. Our hypothesis was that greater absorption of lidocaine would occur from the incision site compared to intact skin. Ten dogs were used in a crossover design. A patch was placed over an incision, and then after a washout period, a patch was placed over intact skin. Plasma lidocaine concentrations were measured at patch placement; 20, 40 and 60 min; and 2, 4, 6, 12, 24, 36, 48, 72 and 96 h after patch placement. After patch removal, the skin was graded using a subjective skin reaction system. No dogs required rescue analgesia, and no toxicity or skin reaction was noted. Mean ± SD AUC and CMAX were 3054.29 ± 1095.93 ng·h/mL and 54.1 ± 15.84 ng/mL in the Incision Group, and 2269.9 ± 1037.08 ng·h/mL and 44.5 ± 16.34 ng/mL in the No-Incision Group, respectively. The AUC was significantly higher in the Incision Group. The results of the study demonstrate that the actual body exposure to lidocaine was significantly higher when an incision was present compared to intact skin. No adverse effects were observed from either treatment. Efficacy was not evaluated., (© 2015 John Wiley & Sons Ltd.)

The intra-articular administration of lidocaine is a frequent practice in human orthopaedic surgical procedures, but an eventual absorption of the drug into the bloodstream can lead to toxicity, mainly concerning the central nervous system and the cardiovascular systems. The purpose of this study was to determine the pharmacokinetic profile and the safety, in terms of cardiovascular and CNS toxicity, of lidocaine after intra-articular administration to anesthetized dogs undergoing arthroscopy. Lidocaine 2% was administered to eight dogs before surgery in differing amounts, depending on the volume of the joints involved, and blood samples were taken at predetermined time points. The maximum serum concentration of lidocaine ranged from 0.50 to 3.01 μg/mL (mean ± SD: 2.18 ± 0.91 μg/mL), and the time to reach it was 28.75 ± 15.74 min. No signs of cardiac toxicity were detected during the entire procedure, and possible signs of CNS toxicity were masked by the anaesthesia. However, concentrations reported in literature as responsible for neurotoxicity in dog were achieved in three of eight investigated subjects. Pending further studies, veterinarians should consider the possibility of side effects occurring following the intra-articular administration of local anaesthetics., (© 2014 John Wiley & Sons Ltd.)

Intra-articular bupivacaine helps alleviate pain in animals receiving joint surgery, but its use has become controversial as ex vivo studies have illuminated the potential for chondrotoxicity. Such studies typically involve cell cultures incubated in solutions containing high bupivacaine concentrations for long durations. The aim of this study was to measure the actual synovial fluid bupivacaine concentrations after intra-articular injection. Eight healthy beagles with normal stifles and 22 large and giant-breed dogs with stifle osteoarthritis (OA) were treated with a single intra-articular injection of bupivacaine (1 mg/kg) into a stifle. Joint fluid samples were taken from the treated stifle immediately after injection and 30 min after injection and analyzed for bupivacaine concentrations. Immediately after injection, the median bupivacaine concentrations in normal and OA stifles were 3.6 and 2.5 mg/mL, respectively. Thirty minutes after injection, bupivacaine concentrations in normal and OA stifles were 0.4 and 0.6 mg/mL, respectively. These results provide insight into the pharmacokinetics of bupivacaine after injection into a joint. Given its immediate dilution and rapid drop in synovial fluid concentration, bupivacaine is unlikely to damage chondrocytes when administered as a single intra-articular injection., (© 2014 John Wiley & Sons Ltd.)

The purpose of this study was to evaluate the pharmacokinetics of lidocaine in mature Holstein cows following an inverted L and caudal epidural nerve block. Plasma and milk concentrations were determined using high-performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following administration via inverted L nerve block, serum T(max) was 0.521 +/- 0.226 h and serum C(max) was 572 +/- 207 ng/mL. Serum AUC was 1348 +/- 335 ng.h/mL. Apparent serum t((1/2)beta) was 4.19 +/- 1.69 h and MRT was 5.13 +/- 2.33 h with clearance uncorrected for the extent of absorption of 2.75 +/- 0.68 L/kg/h. The last measurable time of lidocaine detection in serum was 8.5 +/- 1.4 h with a mean concentration of 51 +/- 30 ng/mL. Milk T(max) was detected at 1.75 +/- 0.46 h with C(max) of 300 +/- 139 ng/mL. Milk AUC till the last time was 1869 +/- 450 ng.h/mL with the mean AUC milk to AUC serum ratio of 1.439 +/- 0.374. The last measurable time of lidocaine detection in milk was 32.5 +/- 16.2 h with a mean concentration of 46 +/- 30 ng/mL. There was no detectable lidocaine concentration in any samples following caudal epidural administration.

Lidocaine patches have been used to provide local analgesia in dogs and cats. We conducted this study to assess the systemic and local absorption of lidocaine from topical patches in cats. Eight 2-year-old cats received either intravenous lidocaine at 2 mg/kg or one 700 mg lidocaine patch placed on the lateral thorax for 72 h, in a cross-over randomized repeated measures design. Plasma was collected at specific times and the skin was biopsied at the time of patch removal for the quantitative analysis of lidocaine and its major metabolite, monoethylglycinexylidide (MEGX), by gas chromatography with mass spectrometry. Percent absorption time plots for systemic lidocaine appearance were constructed using the Loo-Riegelman method. Approximately, constant rate absorption was observed from 12-72 h after patch application at a mean +/- SD rate of 109 +/- 49 microg/kg/h, resulting in steady-state lidocaine plasma concentrations of 0.083 +/- 0.032 microg/mL and MEGX concentrations of 0.012 +/- 0.009 microg/mL. Overall bioavailability of transdermal lidocaine was 6.3 +/- 2.7%, and only 56 +/- 29% of the total lidocaine dose delivered by the patch reached systemic circulation. Skin lidocaine concentrations were much higher than plasma concentrations, at 211 +/- 113 microg/g in the thoracic skin beneath the patch and 2.2 +/- 0.6 microg/g in the contralateral thoracic skin without the patch. As both lidocaine and MEGX were recovered from contralateral skin, it is likely that lidocaine accumulated in the skin from low systemic concentrations of circulating lidocaine over the 72-h period of patch application. Plasma lidocaine concentrations remained well below systemically toxic concentrations, and no obvious clinical side effects were observed in any of the cats. The low systemic absorption rate coupled with high local lidocaine concentrations on the skin support the safe use of lidocaine patches in cats.

Lidocaine is administered as an intravenous infusion to horses for a variety of reasons, but no study has assessed plasma lidocaine concentrations during a 12-h infusion to horses. The purpose of this study was to evaluate the plasma concentrations and pharmacokinetics of lidocaine during a 12-h infusion to postoperative horses. A second purpose of the study was to evaluate the in vitro plasma protein binding of lidocaine in equine plasma. Lidocaine hydrochloride was administered as a loading dose, 1.3 mg/kg over 15 min, then by a constant rate IV infusion, 50 microg/kg/min to six postoperative horses. Lidocaine plasma concentrations were measured by a validated high-pressure liquid chromatography method. One horse experienced tremors and collapsed 5.5 h into the study. The range of plasma concentrations during the infusion was 1.21-3.13 microg/mL. Lidocaine plasma concentrations were significantly increased at 0.5, 4, 6, 8, 10 and 12 h compared with 1, 2 and 3 h. The in vitro protein binding of lidocaine in equine plasma at 2 microg/mL was 53.06+/-10.28% and decreased to 27.33+/-9.72% and 29.52+/-6.44% when in combination with ceftiofur or the combination of ceftiofur and flunixin, respectively. In conclusion, a lower lidocaine infusion rate may need to be administered to horses on long-term lidocaine infusions. The in vitro protein binding of lidocaine is moderate in equine plasma, but highly protein bound drugs may displace lidocaine increasing unbound concentrations and the risk of lidocaine toxicity.

Local anesthesia and tissue inflammation associated with lidocaine infiltration and lidocaine/prilocaine topical anesthetic cream for episioplasty in mares were compared. Twenty-two mares were randomly assigned to lidocaine or lidocaine/prilocaine topical anesthetic cream treatment groups. Perineum and vulva were cleaned, 8-12 g (approximately 1 g/cm per side of vulva) of topical anesthetic cream was applied, and the area was covered by plastic wrap 30 min prior to beginning procedure. Alternately, lidocaine was injected (1 mL) every centimeter just prior to the procedure. Episioplasty was conducted using standard methods, but employing simple interrupted sutures. Horses were not sedated and use of a twitch was recorded. Four millimeter punch biopsies were harvested 1, 3, and 10 days following episioplasty and scored for degree of inflammation by a blinded pathologist. Clinical inflammation scores were assigned when biopsies were obtained. Seven of 11 horses receiving lidocaine infiltration required twitching, but none of the horses that received the anesthetic cream required twitching. Six of 11 and seven of 11 of the lidocaine and anesthetic cream groups, respectively, required twitching for episioplasty. Except for the clinical scores on day 3, no statistical differences for clinical and histopathologic scores between samples from the two treatment groups for a given day were identified. Use of lidocaine/prilocaine topical anesthetic cream was as effective as lidocaine infiltration in providing local anesthesia when performing episioplasty in mares. Its use decreased the need for twitching horses as well as the risk of deformation of the labia caused by lidocaine infiltration.

Bupivacaine is available as a racemic mixture of its enantiomers, d-bupivacaine and l-bupivacaine (LB). The aim of this randomized, double-blind study was to investigate the clinical efficacy and safety of S(-)-bupivacaine compared with standard racemic bupivacaine (RB) in horses under caudal epidural analgesia. Two treatments were administered to each horse, with a 2-week interval between subsequent treatments. Treatment 1 consisted of 0.5% LB at a dose of 0.06 mg/kg of body weight, and treatment 2 consisted of 0.5% RB at a dose of 0.06 mg/kg of body weight. Epidural injections were given in all animals between the first and second coccygeal vertebra. Heart rate (HR), arterial pressures, respiratory rate (RR), rectal temperature (RT), analgesia, and motor blocking were determined before drug administration (basal) and 5, 10, 15 and 30 min after drug administration, and at 30 min intervals thereafter. There were no significant differences between the two treatments in the quality of sensory and motor block. The duration of analgesia was 320 +/- 30 min (mean +/- SD) for RB and 360 +/- 42 min for LB. HRs and RRs, arterial pressures and RT did not change (P < 0.05) significantly from basal values after epidural administration of LB or RB. This study supports that 0.5% LB is an effective alternative to RB in caudal epidural analgesia in conscious, standing horses. The use of LB vs. RB warrants further investigation, particularly for long-lasting surgery in the perineal region.

Topical application of local anesthetics provides safe analgesia following abdominal surgery in people. Conservative doses have been utilized to avoid toxicity. Toxic effects are proportional to amount of drug administered and the plasma concentration of the drug, allowing predictions of safety following pharmacokinetic studies. The maximum plasma level, the pharmacokinetics and the safety of lidocaine hydrochloride when administered by the combined intraperitoneal (8 mg/kg i.p. with epinephrine 1:400 000) and incisional (2 mg/kg with epinephrine 1:200 000) routes were studied in six mixed breed dogs following ovariohysterectomy. Rapid uptake of lidocaine produced a peak concentration of 1.45 +/- 0.36 microg/mL (mean +/- SD, range 0.80-1.86 microg/mL) by 0.37 +/- 0.26 h (range 0.11-0.81) after administration. The absorption half-life was 0.13 +/- 0.1 h. Plasma concentrations decreased rapidly and the elimination half-life was 1.17 +/- 0.11 h. No signs of toxicity were observed in these dogs in the 18 h following drug administration. The dose studied generated levels of lidocaine well below toxic.

Lidocaine is a local anesthetic drug that is widely used in equine medicine. It has the advantage of giving good local anesthesia and a longer duration of action than procaine. Although approved for use in horses in training by the American Association of Equine Practitioners (AAEP), lidocaine is also an Association of Racing Commissioners International (ARCI) Class 2 drug and its detection in forensic samples can result in significant penalties. Lidocaine was observed as a monoprotonated ion at m/z 235 by ESI+ MS/MS (electrospray ionization-positive ion mode) analysis. The base peak ion at m/z 86, representing the postulated methylenediethylamino fragment [CH2N(CH2CH3)2]+, was characteristic of lidocaine and 3-hydroxylidocaine in both ESI+ and EI (electron impact-positive ion mode) mass spectrometry. In addition, we identified an ion at m/z 427 as the principal parent ion of the ion at m/z 86, consistent with the presence of a protonated analog of 3-hydroxylidocaine-glucuronide. We also sought to establish post-administration ELISA-based 'detection times' for lidocaine and lidocaine-related compounds in urine following single subcutaneous injections of various doses (10, 40, 400 mg). Our findings suggest relatively long ELISA based 'detection times' for lidocaine following higher doses of this drug.

Proper veterinary care of horses requires that horses in training have access to modern therapeutic medication. However, the sensitivity of equine drug testing now allows for detection of pharmacologically insignificant concentrations of many therapeutic medications. In 1995, the Association of Racing Commissioners International (ARCI) resolved that members 'address trace level detection so as not to lead to disciplinary action based on pharmacologically insignificant traces of these substances'. The rationale behind this approach is to prevent overly-sensitive testing from inhibiting the proper and appropriate veterinary care of performance horses. This review describes a scientific approach to implement this resolution using local anaesthetics as a model system and compares this approach with others currently in place. For the purpose of this discussion, a 'trace' concentration is defined as a pharmacologically-insignificant concentration. Initially, the target pharmacological effect (e.g. local anaesthesia) was identified, and the dose response relationship was quantified. The 'Highest No Effect Dose' (HNED) was estimated and then administered to horses. Next, the target analyte was identified, synthesized, if necessary, and quantified in blood or urine; the concentrations observed after administration of the HNED are, by definition, true concentrations and hence are pharmacologically insignificant. The key to this approach has been the synthesis of a unique series of authentic equine metabolite standards, which has allowed scientific identification of the concentration at which the pharmacological effect was indistinguishable from control values. Traces found at less than this concentration are, by definition, 'no effect limits', 'no effect traces' (NETs), 'no effect cut-offs', 'no effect limitations on the sensitivity of testing', or 'subtherapeutic residues'. Conversely, this approach will also identify potent medications for which the sensitivity of testing may need to be improved. Within the context of these experiments, the data create an analytical/pharmacological database that should assist industry professionals in interpreting the significance of trace concentrations of these medications or their metabolites in official samples. The most favourable outcome of this research is more medically appropriate use of therapeutic medications in performance horses, yielding substantial benefits to the health and welfare of these horses.

Bupivacaine is a potent local anaesthetic used in equine medicine. It is also classified as a Class 2 foreign substance by the Association of Racing Commissioners International (ARCI). The identification of residues in postrace urine samples may cause regulators to impose significant penalties. Therefore, an analytical/pharmacological database was developed for this medication. The highest no-effect dose (HNED) for the local anaesthetic effect of bupivacaine was determined to be 0.25 mg by using an abaxial sesamoid local anaesthetic model. Administration of the HNED of bupivacaine to eight horses yielded a peak urine concentration of apparent bupivacaine of 23.3 ng/mL 2 h after injection as determined with enzyme-linked immunosorbent assay (ELISA) screening. The major metabolite recovered from beta-glucuronidase-treated equine urine after dosing with bupivacaine is a hydroxybupivacaine, either 3-hydroxybupivacaine, 4-hydroxybupivacaine, or a mixture of the two. To determine which positional isomer occurs in the horse, 4-hydroxybupivacaine was obtained from Maxxam Analytics, Inc., and 3-hydroxybupivacaine was synthesized, purified, and characterized. Furthermore, a quantitative mass spectrometric method was developed for the metabolite as recovered from horse urine. Following subcutaneous injection of the HNED of bupivacaine, the concentration of the hydroxybupivacaine recovered from horse urine reached a peak of 27.4 ng/mL at 4 h after administration as measured by gas chromatography/mass spectrometry (GC/MS). It was also unequivocally demonstrated with ion chromatography that the hydroxybupivacaine metabolite found in horse urine is exclusively 3-hydroxybupivacaine and not 4-hydroxybupivacaine. The mean pH of the 4-h urine samples was 7.21; the mean urine creatinine was 209.5 mg/dL; and the mean urine specific gravity was 1.028. There was no apparent effect of pH, urine creatinine concentration, or specific gravity on the concentration of 3-hydroxybupivacaine recovered. The concentration of bupivacaine or its metabolites after administration of a HNED dose are detectable by mass spectrometric techniques. This study also suggests that recovery of concentrations less than approximately 30 ng/mL of 3-hydroxybupivacaine from postrace urine samples is unlikely to be associated with a recent local anaesthetic effect of bupivacaine.

Mepivacaine is a local anaesthetic drug that is widely used in equine medicine and is classified by the Association of Racing Commissioners International (ARCI) as a Class 2 foreign substance that may cause regulators to impose significant penalties if residues are identified in post-race urine samples. Therefore, an analytical/pharmacological database was developed for this agent and its metabolites. Using an abaxial sesamoid local anaesthetic model, it was determined that the highest no-effect dose (HNED) for its local anaesthetic effect was 2 mg. Using enzyme-linked immunosorbent assay (ELISA) screening, it was determined that subcutaneous (s.c.) administration of the HNED of mepivacaine to eight horses yielded a peak urinary concentration of apparent mepivacaine of 63 ng/mL 2 h after injection. The major identified metabolite recovered from equine urine after dosing with mepivacaine is 3-hydroxymepivacaine. Therefore, 3-hydroxymepivacaine was synthesized, purified and characterized, and a quantitative mass spectrometric method was developed for this metabolite as isolated from horse urine. Following subcutaneous injection of the HNED of mepivacaine, the concentration of 3-hydroxymepivacaine recovered from horse urine reached a peak of about 64.6 ng/mL at 4 h after administration as measured by GC/MS. The concentration of mepivacaine or its metabolites after administration of a HNED dose are detectable by mass spectral techniques. Within the limits of this research, the study suggests that recovery of concentrations less than about 65 ng/mL of 3-hydroxymepivacaine from post-race urine samples may not be associated with a recent LA effect of mepivacaine.

Fentanyl and other opioid drugs have their effect in the central nervous system; however, activity at peripheral sites has also been demonstrated. Pain-suppression activity at peripheral sites raises the possibility of skilled individuals producing local anaesthetic effects with small doses of opioid drugs that would be difficult to detect forensically and could be used to affect the outcome of a race. Therefore, the local pain-suppression effect (peripheral nerve inhibition) of fentanyl was tested using an abaxial sesamoid block/hoof withdrawal model. With this model, fentanyl did not produce significant anaesthesia when tested in eight Thoroughbred horses. This suggests that fentanyl at this or lower doses is unlikely to reduce pain perception when applied directly to sensory neurons. However, the effect of fentanyl and other opioids on joint pain perception of horses, especially inflamed joints, is unknown.

Lidocaine is a local anaesthetic agent that is widely used in equine medicine. It is also an Association of Racing Commissioners International (ARCI) Class 2 foreign substance that may cause regulators to impose substantial penalties if residues are identified in post race urine samples. Therefore, an analytical/pharmacological database was developed for this drug. Using our abaxial sesamoid local anaesthetic model, the highest no-effect dose (HNED) for the local anaesthetic effect of lidocaine was determined to be 4 mg. Using enzyme-linked immunosorbent assay (ELISA) screening, administration of the HNED of lidocaine to eight horses yielded peak serum and urine concentrations of apparent lidocaine of 0.84 ng/mL at 30 min and 72.8 ng/mL at 60 min after injection, respectively. These concentrations of apparent lidocaine are readily detectable by routine ELISA screening tests (LIDOCAINE ELISA, Neogen, Lexington, KY). ELISA screening does not specifically identify lidocaine or its metabolites, which include 3-hydroxylidocaine, dimethylaniline, 4-hydroxydimethylaniline, monoethylglycinexylidine, 3-hydroxymonoethylglycinexylidine, and glycinexylidine. As 3-hydroxylidocaine is the major metabolite recovered from equine urine, it was synthesized, purified and characterized, and a quantitative mass spectrometric method was developed for 3-hydroxylidocaine as recovered from horse urine. Following subcutaneous (s.c.) injection of the HNED of lidocaine, the concentration of 3-hydroxylidocaine recovered from urine reached a peak of about 315 ng/mL at 1 h after administration. The mean pH of the 1 h post dosing urine samples was 7. 7, and there was no apparent effect of pH on the amount of 3-hydroxylidocaine recovered. Within the context of these experiments, the data suggests that recovery of less than 315 ng/mL of 3-hydroxylidocaine from a post race urine sample is unlikely to be associated with a recent local anaesthetic effect of lidocaine. Therefore these data may be of assistance to industry professionals in evaluating the significance of small concentrations of lidocaine or its metabolites in postrace urine samples. It should be noted that the quantitative data are based on analytical methods developed specifically for this study, and that methods used by other laboratories may yield different recoveries of urine 3-hydroxylidocaine.

The pharmacokinetics of benzocaine during bath exposures at 1 mg/L were determined in rainbow trout acclimated at 6 degrees C, 12 degrees C or 18 degrees C for at least 1 month. Individual fish were exposed to benzocaine in a recirculating system for 4 h and pharmacokinetic parameters were estimated in a unique manner from the concentration of benzocaine in the bath water vs. time curve. Elimination from plasma was also determined after the 4 h exposure. The uptake clearance and metabolic clearance increased with increased acclimatization temperatures (uptake clearance 581 +/- 179 mL/min/kg at 6 degrees C and 1154 +/- 447 mL/min/kg at 18 degrees C; metabolic clearance 15.2 +/- 4.1 mL/min/kg at 6 degrees C and 22.3 +/- 4.2 mL/min/kg at 18 degrees C). The apparent volume of distribution had a trend for increasing with temperature that was not significant at the 5% level (2369 +/- 678 mL/kg at 6 degrees C to 3260 +/- 1182 mL/kg at 18 degrees C). The elimination half-life of benzocaine in plasma was variable and did not differ significantly with temperature (60.8 +/- 30.3 min at 6 degrees C to 35.9 +/- 13.0 min at 12 degrees C). Elimination of benzocaine from rainbow trout is relatively rapid and even more rapid at higher acclimatization temperatures based on calculated metabolic clearances and measured plasma concentrations, but was not evident by measurement of terminal plasma half-lifes.

The elimination kinetics and the formation of the monoethylglycinexylidide (MEGX), a major metabolite of lidocaine, were studied in camels deprived of water for 14 days. The study was conducted on four camels in a crossover design. Lidocaine was administered intravenously at a dose of 1 mg/kg to adult female camels when water was given ad libitum (stage 1) and to the same camels after 14 days of dehydration. Blood samples were taken up to 6 h after dosing. Serum lidocaine and MEGX levels were analysed by polarization fluorescence immunoassay. The elimination profiles of lidocaine and the formation of the metabolite MEGX in the two phases of the study were essentially identical. No difference in any pharmacokinetic parameter was noticed between normally hydrated and water-deprived camels. It is thus concluded that dehydration does not affect the cytochrome P450 isozymes involved in degradation of lidocaine to MEGX nor does it affect the hepatic blood flow, which is a major determinant in the clearance of lidocaine. The very low clearance of lidocaine in the camel in comparison with other ruminant or monogastric mammals may be associated with the camel's ability to survive drought in the desert.