The effects of inhibiting cytochrome P450 3A, p‐glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

KuKanich, Butch; Lascelles, B. Duncan X.; Aman, Alisha; Mealey, Katrina L.; Papich, Mark G.

doi:10.1111/j.1365-2885.2005.00681.x

Cited by 69 publications

(59 citation statements)

References 37 publications

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“…For these compounds, the marked interspecies difference in oral bioavailability is the result of a high first-pass metabolism in dogs (42,64), a characteristic of oral opiates in dogs that is not as prominent in humans. Other oral opiates not included in this analysis also have essentially zero oral systemic availability in dogs (86,87). For these drugs, systemic clearance exceeds liver blood flow and there may be extrahepatic metabolism contributing to the high first-pass metabolism.…”

Section: Discussionmentioning

confidence: 99%

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

Papich

Martinez

2015

AAPS J

115

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Abstract. The Biopharmaceutical Classification System (BCS) has been a prognostic tool for assessing the potential effects of formulation on the human drug oral bioavailability. When used in conjunction with in vitro dissolution tests, the BCS can support the prediction of in vivo product performance and the development of mechanistic models that support formulation assessments through the generation of Bwhat if^scenarios. To date, the applicability of existing human BCS criteria has not been evaluated in dogs, thereby limiting its use in canine drug development. Therefore, we examined 50 drugs for which absolute bioavailability (F) was available both in dogs and humans. The drugs were also evaluated for any potential association between solubility (calculated from the dose number, Do) or lipophilicity (LogP) and F in dogs. In humans, solubility is determined in 250 mL of fluid. However, the appropriate volume for classifying drug solubility in dogs has not been established. In this analysis, the estimated volume of a water flush administered to fasted dogs (6 mL) and a volume of 250 mL scaled to a Beagle dog (35 mL) were examined. In addition, in humans, a Do value greater than 1.0 is used to define a compound as highly soluble and a LogP value greater than 1.72 as high permeability. These same criteria were applied for defining highly soluble and highly permeable in dogs. Whether using 35 or 6 mL to determine Do, the canine solubility classification remained unchanged for all but seven compounds. There were no clear associations between a drug's F in dogs and humans or between the canine value of F and either its human BCS classification, its LogP value, or the canine Do estimate. There was a tendency for those drugs with canine values of F equal to or greater than 80% to have LogP values equal to or greater than 1.0. Exceptions to this observation tended to be those compounds known to be absorbed via mechanisms other than passive diffusion (e.g., via transporters or paracellular transporters). Although there are limitations to the approach used in this study, the results of our assessment strongly suggest that the human BCS classification system requires substantial modification before it can be reliably applied to dogs.

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Section: Discussionmentioning

confidence: 99%

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

Papich

Martinez

2015

AAPS J

115

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“…Secondly, it is suggested that morphine is poorly and erratically absorbed from the gastrointestinal tract, particularly following administration of sustained release tablets. These data for morphine are matched by data following oral administration of other opioids to dogs, for example methadone (Kukanich and others 2005a). …”

Section: Options For Medium-term Opioid Analgesia In Discharged Dogsmentioning

confidence: 99%

Extending postoperative opioid analgesia in dogs 1. Oral drug administration

Murrell¹,

Flaherty²

2014

In Practice

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Although opioid drugs are extensively used for postoperative analgesia in dogs, their administration is generally restricted to the period in which the animal is hospitalised. Unfortunately, this limits the ability to provide multimodal pain relief in the home environment, which may lead to inadequate analgesia and consequent ‘break-through’ pain. This article, the first in a series of two, discusses the uses and limitations of oral opioid administration for extending postoperative analgesia beyond the hospitalisation period. The second article, to be published in a subsequent issue of In Practice, will focus on the role of transdermal opioid delivery for this purpose.

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“…Valspodar was also found to increase the bioavailability and analgesic effects of methadone in rats (148). Conversely, the pharmacokinetics of methadone in dogs was unaffected by P-gp inhibition (221).…”

Section: Methadonementioning

confidence: 96%

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

et al. 2015

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Opioid-related deaths, abuse, and drug interactions are growing epidemic problems that have medical, social, and economic implications. Drug transporters play a major role in the disposition of many drugs, including opioids; hence they can modulate their pharmacokinetics, pharmacodynamics and their associated drug-drug interactions (DDIs). Our understanding of the interaction of transporters with many therapeutic agents is improving; however, investigating such interactions with opioids is progressing relatively slowly despite the alarming number of opioids-mediated DDIs that may be related to transporters. This review presents a comprehensive report of the current literature relating to opioids and their drug transporter interactions. Additionally, it highlights the emergence of transporters that are yet to be fully identified but may play prominent roles in the disposition of opioids, the growing interest in transporter genomics for opioids, and the potential implications of opioid-drug transporter interactions for cancer treatments. A better understanding of drug transporters interactions with opioids will provide greater insight into potential clinical DDIs and could help improve opioids safety and efficacy.

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The effects of inhibiting cytochrome P450 3A, p‐glycoprotein, and gastric acid secretion on the oral bioavailability of methadone in dogs

Cited by 69 publications

References 37 publications

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

Applying Biopharmaceutical Classification System (BCS) Criteria to Predict Oral Absorption of Drugs in Dogs: Challenges and Pitfalls

Extending postoperative opioid analgesia in dogs 1. Oral drug administration

Transporter-Mediated Disposition of Opioids: Implications for Clinical Drug Interactions

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