Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine‐6‐glucuronide in healthy Greyhound dogs

KuKanich, B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine‐6‐glucuronide in healthy Greyhound dogs. J. vet. Pharmacol. Therap . 33 , 15–21. The purpose of this study was to determine the pharmacokinetics of codeine and the active metabolites morphine and codeine‐6‐glucuronide after i.v. codeine administration and the pharmacokinetics of acetaminophen (APAP), codeine, morphine, and codeine‐6‐glucuronide after oral administration of combination product containing acetaminophen and codeine to dogs. Six healthy Greyhound dogs were administered 0.734 mg/kg codeine i.v. and acetaminophen (10.46 mg/kg mean dose) with codeine (1.43 mg/kg mean dose) orally. Blood samples were collected at predetermined time points for the determination of codeine, morphine, and codeine‐6‐glucuronide plasma concentrations by LC/MS and acetaminophen by HPLC with UV detection. Codeine was rapidly eliminated after i.v. administration ( T ½ = 1.22 h; clearance = 29.94 mL/min/kg; volume of distribution = 3.17 L/kg) with negligible amounts of morphine present, but large amounts of codeine‐6‐glucuronide ( C max  = 735.75 ng/mL) were detected. The oral bioavailability of codeine was 4%, morphine concentrations were negligible, but large amounts of codeine‐6‐glucuronide ( C max  = 1952.86 ng/mL) were detected suggesting substantial first pass metabolism. Acetaminophen was rapidly absorbed ( C max  = 6.74 μg/mL; T max  = 0.85 h) and eliminated ( T ½ = 0.96 h). In conclusion, the pharmacokinetics of codeine was similar to other opioids in dogs with a short half‐life, rapid clearance, large volume of distribution, and poor oral bioavailability. High concentrations of codeine‐6‐glucuronide were detected after i.v. and oral administration.