The influence of modulation of P‐glycoprotein and /or Cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs

Abstract

The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P-glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P < 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-∞) ) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores.

Extending postoperative opioid analgesia in dogs 1. Oral drug administration

“…One strategy that has been applied to try and increase oral bioavailability of opioids in dogs is to coadminister the opioid with drugs that modulate the metabolism of opioids, for example with a drug that is an inhibitor of the cytochrome P450 enzyme system in the liver (Kukanich and others 2011) or an inhibitor of P-glycoprotein (Gadeyne and others 2011), a drug efflux pump that may limit absorption of morphine through gut enterocytes. Unfortunately, these novel strategies have failed to yield positive results so far.…”

The Effect of Morphine on Regional Cerebral Blood Flow Measured by 99mTc-ECD SPECT in Dogs

“…Plasma and CSF concentrations of morphine were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, as previously described by Gadeyne et al [25] . Quality control (QC) and blank samples were analyzed together with each batch of incurred samples to check the extraction and LC-MS/MS procedure.…”

Pharmacogenetics of opioid analgesics in dogs

“…In dogs, both in vivo and in vitro studies identified ketoconazole to be P-gp inhibitor (Kuroha, Azumano, Kuze, Shimoda, & Kokue, 2002;Kuroha, Shirai, & Shimoda, 2004). It has been used as a probe to assess the effect of P-gp inhibition on pharmacokinetics and pharmacodynamics of morphine (IV, PO), fentanyl (IV) and methadone (PO) in greyhound and beagle dogs (Gadeyne et al, 2011;Kukanich & Borum, 2008;Kukanich & Hubin, 2010;KuKanich et al, 2005) . No significant changes in disposition of these opioids were found in all studies.…”

“…No significant changes in disposition of these opioids were found in all studies. Prolonged and increased sedation has been observed in dogs treated with ketoconazole prior to morphine administration (Gadeyne et al., ).…”