Evaluation of pharmacokinetics of metoclopramide administered via subcutaneous bolus and intravenous constant rate infusion to adult horses.

OBJECTIVE: To determine the pharmacokinetics (PK) of metoclopramide administered via intravenous continuous rate infusion (IV CRI) and subcutaneous (SC) bolus and evaluate for gastrointestinal motility and adverse side effects. STUDY DESIGN: Experimental study; randomized, crossover design. ANIMALS: Six healthy adult horses. METHODS: Each horse received metoclopramide via IV CRI (0.04 mg/kg/h for 24 h) and SC bolus (0.08 mg/kg once), with ≥1 week washout period between. Plasma was analyzed by UPLC-MS/MS. Compartmental modeling was used to determine PK parameters for each treatment; nonparametric superposition was used to simulate multiple SC bolus regimens. Gastrointestinal motility and evidence of adverse effects were monitored. RESULTS: Tmax (h) for SC bolus was 0.583 ± 0.204 versus 17.3 ± 6.41 for IV CRI, while Cmax (ng/mL) was 27.7 ± 6.38 versus 43.6 ± 9.97, respectively. AUC (h × ng/mL) was calculated as 902 ± 189 for 24 h IV CRI versus 244 ± 37.4 simulated for 0.08 mg/kg SC bolus every 8 h. Simulations revealed similar exposure between groups with administration of 0.96 mg/kg/day SC bolus, divided into three, four, or six doses. SC bolus bioavailability was estimated as 110 ± 11.5%. No clear trends in motility alteration were identified. No adverse effects were noted. CONCLUSION: Repeated SC boluses of metoclopramide at 0.08 mg/kg would result in lower total drug exposure and Tmax than IV CRI administration but would be highly bioavailable. CLINICAL SIGNIFICANCE: Higher and/or more frequent SC bolus doses are needed to achieve a similar AUC to IV CRI. No adverse effects were noted; however, evaluation of alternative dosing strategies is warranted.

Simultaneous genotyping of single nucleotide polymorphisms in the IL-1 gene complex by multiplex polymerase chain reaction-restriction fragment length polymorphism.

The interleukin-1 (IL-1) gene complex consists of the IL-1alpha, IL-1beta and IL-1 receptor antagonist genes. Single-nucleotide polymorphisms (SNP) in all three genes have been associated with human diseases. In this study, primers containing mismatches at 1-3 nucleotide positions were designed to incorporate a restriction site for endonuclease AlwNI or XcmI in the presence of allele-specific nucleotides at the polymorphic positions. Based on this technique, a simple and robust multiplex polymerase chain reaction/restriction fragment length polymorphism (multiplex PCR/RFLP) assay was developed to determine simultaneously three to four informative SNPs (IL-1beta/+3954, IL-1beta/-511 and IL-1Ra/9261 or IL-1alpha/-889, IL-1beta/-31, IL-1beta/5810 and IL-1Ra/11100 SNPs) in the IL-1 gene complex.