Pharmacokinetics and pharmacodynamics of repeat dosing of gabapentin in adult horses.

BACKGROUND: The repeated administration of high doses of gabapentin may provide better analgesia in horses than current clinical protocols. HYPOTHESIS AND OBJECTIVES: Administration of gabapentin at 40 and 120 mg/kg PO q 12 h for 14 days will not alter serum biochemistry findings or cause adverse effects. Our objectives were to evaluate the effect of gabapentin on serum biochemistry, physical examination, and plasma pharmacokinetics of gabapentin. ANIMALS: Six healthy adult mares. METHODS: Horses received 40 and 120 mg/kg of gabapentin orally q 12 h for 14 days. Horses were examined and scored for ataxia and sedation daily. Serum biochemistry variables were analyzed before treatment and days 7 and 14 after gabapentin administration. Plasma disposition of gabapentin was evaluated after the first and last drug administration. Pharmacokinetic parameters were estimated using noncompartmental analysis. RESULTS: No changes occurred in physiologic or biochemical variables. Median (range) maximal plasma gabapentin concentrations (µg/mL) after the last dose (day 15) were 7.6 (6.2-11) and 22 (14-33) for 40 mg/kg and 120 mg/kg doses respectively. Maximal concentration of gabapentin was reached within 1 hour after drug administration. Repeated administration of gabapentin resulted in a median (range) area under the curve (AUC0-12 hours ) last/first dose ratio of 1.5 (1.00-2.63) and 2.92 (1.4-3.8) for the 40 and 120 mg/kg regimens, respectively. CONCLUSION AND CLINICAL IMPORTANCE: Our results suggest that horses tolerate gabapentin up to 120 mg/kg PO q 12 h for 14 days. The analgesic effect of the dosage regimens evaluated in our study warrants further research.

Plasma disposition of gabapentin after the intragastric administration of escalating doses to adult horses.

BACKGROUND: In humans, gabapentin an analgesic, undergoes non-proportional pharmacokinetics which can alter efficacy. No information exists on the pharmacokinetics of dosages >20 mg/kg, escalating dosages or dose proportionality of gabapentin in horses. HYPOTHESIS AND OBJECTIVES: Gabapentin exposure in plasma would not increase proportionally relative to the dose in horses receiving dosages ≥20 mg/kg. To assess the plasma pharmacokinetics of gabapentin after nasogastric administration of gabapentin at dosages of 10 to 160 mg/kg in adult horses. ANIMALS: Nine clinically healthy adult Arabian and Quarter Horses. METHODS: In a randomized blinded trial, gabapentin was administered by nasogastric intubation to horses at 10, 20 mg/kg (n = 3) and 60, 80, 120, 160 mg/kg (n = 6). Plasma was collected before and at regular times over 64 hours after administration of gabapentin. Gabapentin was quantified using a validated chromatographic method. Dose proportionality was estimated using a power model. Pharmacokinetic parameters were estimated using compartmental pharmacokinetic analysis. RESULTS: Plasma pharmacokinetics parameters of gabapentin were estimated after nasogastric administration at dosages of 10 to 160 mg/kg. Gabapentin plasma concentration increased with dose increments. However, the area under the concentration curve from zero to infinity and maximal plasma concentration did not increase proportionally relative to the dose in horses. CONCLUSIONS AND CLINICAL IMPORTANCE: Gabapentin exposure in plasma is not proportional relative to the dose in horses receiving nasogastric dosages of 10 to 160 mg/kg.

Effects of ventilation mode and blood flow on arterial oxygenation during pulse-delivered inhaled nitric oxide in anesthetized horses.

OBJECTIVE To determine the impact of mechanical ventilation (MV) and perfusion conditions on the efficacy of pulse-delivered inhaled nitric oxide (PiNO) in anesthetized horses. ANIMALS 27 healthy adult horses. PROCEDURES Anesthetized horses were allocated into 4 groups: spontaneous breathing (SB) with low (< 70 mm Hg) mean arterial blood pressure (MAP; group SB-L; n = 7), SB with physiologically normal (≥ 70 mm Hg) MAP (group SB-N; 8), MV with low MAP (group MV-L; 6), and MV with physiologically normal MAP (group MV-N; 6). Dobutamine was used to maintain MAP > 70 mm Hg. Data were collected after a 60-minute equilibration period and at 15 and 30 minutes during PiNO administration. Variables included Pao2, arterial oxygen saturation and content, oxygen delivery, and physiologic dead space-to-tidal volume ratio. Data were analyzed with Shapiro-Wilk, Mann-Whitney U, and Friedman ANOVA tests. RESULTS Pao2, arterial oxygen saturation, arterial oxygen content, and oxygen delivery increased significantly with PiNO in the SB-L, SB-N, and MV-N groups; were significantly lower in group MV-L than in group MV-N; and were lower in MV-N than in both SB groups during PiNO. Physiologic dead space-to-tidal volume ratio was highest in the MV-L group. CONCLUSIONS AND CLINICAL RELEVANCE Pulmonary perfusion impacted PiNO efficacy during MV but not during SB. Use of PiNO failed to increase oxygenation in the MV-L group, likely because of profound ventilation-perfusion mismatching. During SB, PiNO improved oxygenation irrespective of the magnitude of blood flow, but hypoventilation and hypercarbia persisted. Use of PiNO was most effective in horses with adequate perfusion.

Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O-Desmethyltramadol Metabolite in Healthy Dogs.

Tramadol is used frequently in the management of mild to moderate pain conditions in dogs. This use is controversial because multiple reports in treated dogs demonstrate very low plasma concentrations of O-desmethyltramadol (M1), the active metabolite. The objective of this study was to identify a drug that could be coadministered with tramadol to increase plasma M1 concentrations, thereby enhancing analgesic efficacy. In vitro studies were initially conducted to identify a compound that inhibited tramadol metabolism to N-desmethyltramadol (M2) and M1 metabolism to N,O-didesmethyltramadol (M5) without reducing tramadol metabolism to M1. A randomized crossover drug-drug interaction study was then conducted by administering this inhibitor or placebo with tramadol to 12 dogs. Blood and urine samples were collected to measure tramadol, tramadol metabolites, and inhibitor concentrations. After screening 86 compounds, fluconazole was the only drug found to inhibit M2 and M5 formation potently without reducing M1 formation. Four hours after tramadol administration to fluconazole-treated dogs, there were marked statistically significant (P < 0.001; Wilcoxon signed-rank test) increases in plasma tramadol (31-fold higher) and M1 (39-fold higher) concentrations when compared with placebo-treated dogs. Conversely, plasma M2 and M5 concentrations were significantly lower (11-fold and 3-fold, respectively; P < 0.01) in fluconazole-treated dogs. Metabolite concentrations in urine followed a similar pattern. This is the first study to demonstrate a potentially beneficial drug-drug interaction in dogs through enhancing plasma tramadol and M1 concentrations. Future studies are needed to determine whether adding fluconazole can enhance the analgesic efficacy of tramadol in healthy dogs and clinical patients experiencing pain.

Pharmacokinetics and physiologic/behavioral effects of buprenorphine administered sublingually and intravenously to neonatal foals.

Buprenorphine is absorbed following sublingual administration, which would be a low-stress delivery route in foals. However, the pharmacokinetics/pharmacodynamics are not described in foals. Six healthy foals <21 days of age participated in a blinded, randomized, 3-period, 5-sequence, 3-treatment crossover prospective study. Foals received 0.01-0.02 mg/kg buprenorphine administered SL or IV with an equivalent volume of saline administered by the opposite route. Blood was collected from the cephalic vein for pharmacokinetic analysis. Physiologic parameters (HR, RR, body temperature, GI sounds), locomotion (pedometer), and behavioral data (activity level, nursing time, response to humans) were recorded. Plasma concentration of buprenorphine exceeded a presumed analgesic level (0.6 ng/ml) in five foals in the IV group and one in the SL group but only for a very brief time. Pharmacokinetic analysis following IV administration demonstrated a short elimination half-life (t1/2ß 1.95 ± 0.7 hr), large volume of distribution (6.46 ± 1.54 L/kg), and a high total clearance (55.83 ± 23.75 ml/kg/min), which differs from adult horses. Following SL administration, maximum concentrations reached were 0.61 ± 0.11 ng/ml and bioavailability was 25.1% ± 10.9%. In both groups, there were minor statistical differences in HR, RR, body temperature, locomotion, and time spent nursing. However, these differences were clinically insignificant in this single dose study, and excitement, sedation, or colic did not occur.

Identification of canine cytochrome P-450s (CYPs) metabolizing the tramadol (+)-M1 and (+)-M2 metabolites to the tramadol (+)-M5 metabolite in dog liver microsomes.

We previously showed that (+)-tramadol is metabolized in dog liver to (+)-M1 exclusively by CYP2D15 and to (+)-M2 by multiple CYPs, but primarily CYP2B11. However, (+)-M1 and (+)-M2 are further metabolized in dogs to (+)-M5, which is the major metabolite found in dog plasma and urine. In this study, we identified canine CYPs involved in metabolizing (+)-M1 and (+)-M2 using recombinant enzymes, untreated dog liver microsomes (DLMs), inhibitor-treated DLMs, and DLMs from CYP inducer-treated dogs. A canine P-glycoprotein expressing cell line was also used to evaluate whether (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 are substrates of canine P-glycoprotein, thereby limiting their distribution into the central nervous system. (+)-M5 was largely formed from (+)-M1 by recombinant CYP2C21 with minor contributions from CYP2C41 and CYP2B11. (+)-M5 formation in DLMs from (+)-M1 was potently inhibited by sulfaphenazole (CYP2C inhibitor) and chloramphenicol (CYP2B11 inhibitor) and was greatly increased in DLMs from phenobarbital-treated dogs. (+)-M5 was formed from (+)-M2 predominantly by CYP2D15. (+)-M5 formation from (+)-M1 in DLMs was potently inhibited by quinidine (CYP2D inhibitor) but had only a minor impact from all CYP inducers tested. Intrinsic clearance estimates showed over 50 times higher values for (+)-M5 formation from (+)-M2 compared with (+)-M1 in DLMs. This was largely attributed to the higher enzyme affinity (lower Km) for (+)-M2 compared with (+)-M1 as substrate. (+)-tramadol, (+)-M1, (+)-M2, or (+)-M5 were not p-glycoprotein substrates. This study provides a clearer picture of the role of individual CYPs in the complex metabolism of tramadol in dogs.

Comparison of Enterprise Point-of-Care and Nova Biomedical Critical Care Xpress analyzers for determination of arterial pH, blood gas, and electrolyte values in canine and equine blood.

BACKGROUND: Point-of-care analyzers can provide a rapid turnaround time for critical blood test results. Agreement between the Enterprise Point-of-Care (EPOC) and bench-top laboratory analyzers is important to determine the clinical reliability of the EPOC. OBJECTIVES: The aim of the study was (1) to evaluate the precision (repeatability) of blood gas values measured by the EPOC and (2) to determine the level of agreement between the EPOC and Nova Critical Care Express (Nova CCX) for the assessment of arterial pH, blood gases, and electrolyte variables in canine and equine blood. METHODS: Arterial blood samples from dogs were analyzed on the EPOC and Nova CCX analyzers to determine precision and agreement of pH, PaCO2 , PaO2 , and HCT. The same analytes plus Na+ , K- , and Cl- were analyzed for agreement using equine blood. Statistical analyses included assessment of precision using the coefficient of variation (CV%), and agreement using the Deming regression, Pearson correlation, and Bland-Altman plots. RESULTS: Both analyzers provided precise results of pH, PaCO2 , PaO2, and HCT, meeting CV% quality requirement values. In both species, Deming regression results were acceptable and correlation values were above 0.93 for arterial pH and blood gases, but lower for sodium and chloride. Bland-Altman plots demonstrated varying degrees of bias, but good agreement between the 2 analyzers was seen when arterial blood gases and electrolytes were measured, except for PaCO2 and Cl-. CONCLUSION: The EPOC analyzer provides consistent, reliable results for canine arterial blood gas values and for equine arterial blood gas and electrolyte values. Cl- results could be acceptable with the application of a correction factor, but the PaCO2 results were more variable.

Assessment of clinical application of pulse oximetry probes in llamas and alpacas.

The placement and accuracy of pulse oximeter probes can vary markedly among species. For our study, we aimed to assess the accuracy of pulse oximetry and to determine the most clinically useful sites for probe placement in llamas and alpacas. The objectives included an analysis of pulse oximetry probes for accurate assessment of llamas and alpacas and to determine the best placement of the probes to achieve accurate readings. For study 1, saturation of haemoglobin with oxygen was measured in 184 arterial blood gas samples (SaO2) using a co-oximeter and compared to saturation of haemoglobin with oxygen simultaneously measured using a pulse oximeter (SpO2). The bias and precision for the SpO2-SaO2 difference was calculated and plotted on a Bland-Altman plot. For study 2, SpO2 data was collected 624 times from a variety of sites [tongue (T), nasal septum (NS), lip (L), vulva (V), prepuce (P), ear (E), and scrotum (S)] and recorded based upon a percentage of successful readings. Results for study 1 revealed that SpO2 was consistently 0 to -6% points different than SaO2. The bias and precision of the SpO2-SaO2 difference was -2.6 ± 1.7%. Results for study 2 uncovered that 540 recordings were successful readings and were obtained from the tongue and nasal septum with 97% accuracy, the lip 80%, vulva 62%, prepuce 59%, ear and scrotum < 50%. We concluded that pulse oximetry probes provide reliable estimates of arterial haemoglobin oxygen saturation in llamas and alpacas and is most accurately read when placed on the nasal septum or tongue.

Relationship between the melanocortin-1 receptor (MC1R) variant R306ter and physiological responses to mechanical or thermal stimuli in Labrador Retriever dogs.

OBJECTIVE: Variants in the MC1R gene have been associated with red hair color and sensitivity to pain in humans. The study objective was to determine if a relationship exists between MC1R genotype and physiological thermal or mechanical nociceptive thresholds in Labrador Retriever dogs. STUDY DESIGN: Prospective experimental study. ANIMALS: Thirty-four Labrador Retriever dogs were included in the study following public requests for volunteers. Owner consent was obtained and owners verified that their dog was apparently not experiencing pain and had not been treated for pain during the previous 14 days. The study was approved by the Institutional Animal Care and Use Committee. METHODS: Nociceptive thresholds were determined from a mean of three thermal and five mechanical replications using commercially available algometers. Each dog was genotyped for the previously described MC1R variant (R306ter). Data were analyzed using one-way anova with post hoc comparisons using Tukey's test (p < 0.05). RESULTS: Thirteen dogs were homozygous wild-type (WT/WT), nine were heterozygous (WT/R306ter), and eight were homozygous variant (R306ter/R306ter) genotype. Four dogs could not be genotyped. A significant difference (p = 0.04) in mechanical nociceptive thresholds was identified between dogs with the WT/WT genotype (12.1±2.1 N) and those with the WT/R306ter genotype (9.2±2.4 N). CONCLUSION: A difference in mechanical, but not thermal, nociceptive threshold was observed between wild-type and heterozygous MC1R variants. Differences in nociceptive thresholds between homozygous R306ter variants and other genotypes for MC1R were not observed. CLINICAL RELEVANCE: Compared with the wild-type MC1R genotype, nociceptive sensitivity to mechanical force in dogs with a single variant R306ter allele may be greater. However, in contrast to the reported association between homozygous MC1R variants (associated with red hair color) and nociception in humans, we found no evidence of a similar relationship in dogs with the homozygous variant genotype.

Tramadol metabolism to O-desmethyl tramadol (M1) and N-desmethyl tramadol (M2) by dog liver microsomes: Species comparison and identification of responsible canine cytochrome P-450s (CYPs).

Tramadol is widely used to manage mild to moderately painful conditions in dogs. However, this use is controversial since clinical efficacy studies in dogs showed conflicting results, while pharmacokinetic studies demonstrated relatively low circulating concentrations of O-desmethyltramadol (M1). Analgesia has been attributed to the opioid effects of M1, while tramadol and the other major metabolite (N-desmethyltramadol, M2) are considered inactive at opioid receptors. The aims of this study were to determine whether cytochrome P450 (CYP) dependent M1 formation by dog liver microsomes is slower compared with cat and human liver microsomes; and identify the CYPs responsible for M1 and M2 formation in canine liver. Since tramadol is used as a racemic mixture of (+)- and (-)-stereoisomers, both (+)-tramadol and (-)- tramadol were evaluated as substrates. M1 formation from tramadol by liver microsomes from dogs was slower than from cats (3.9-fold), but faster than humans (7-fold). However, M2 formation by liver microsomes from dogs was faster than from cats (4.8-fold) and humans (19-fold). Recombinant canine CYP activities indicated that M1 was formed by CYP2D15, while M2 was largely formed by CYP2B11 and CYP3A12. This was confirmed by dog liver microsomes studies that showed selective inhibition of M1 formation by quinidine and M2 formation by chloramphenicol and CYP2B11 antiserum, and induction of M2 formation by phenobarbital. Findings were similar for both (+)-tramadol and (-)-tramadol. In conclusion, low circulating M1 concentrations in dogs is explained in part by low M1 formation and high M2 formation, which are mediated by CYP2D15 and CYP2B11/CYP3A12, respectively.