Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

Tibbitts, Jay

doi:10.1080/01926230390174896

Cited by 35 publications

(39 citation statements)

References 45 publications

(43 reference statements)

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“…The folly of simple comparisons based upon limited databases is illustrated by data in the same publication where oxidation rates between liver microsomes of the cynomolgus monkey and man were more similar than the other species included in the study if CYP oxidative activity was referred back to total CYP content in the livers. The guiding principle in the selection of the most suitable species for these types of studies would appear to be that each chemical/drug needs to be taken on a case-by-case basis if accurate representation of the human hepatic metabolism is the desired outcome (Tibbets, 2003).…”

Section: Drug-induced Nonneoplastic Hepatic Changesmentioning

confidence: 99%

“…Of consideration when selecting a suitable species as the nonrodent is the similarity to man in terms of metabolism, pharmacology etc., cost, experience in terms of familiarity with the foibles of the particular species chosen, and the existence of 63 64 FOSTER TOXICOLOGIC PATHOLOGY background disease, are important considerations if interpretation of the results of such studies is not to be compromised (Lowenstine, 2003). There is no such thing as an ideal surrogate species for man and while nonhuman primates are phylogenetically closer to man than is the dog, numerous examples exist where the latter has proven to be more predictive than have been subsequent primate studies (Bogaards et al, 2000;Tibbets, 2003), particularly in terms of pharmacokinetic parameters of absorption and metabolism. Part of the problem pertinent to primate studies is that there are a number of species available, all of which have particular advantages and disadvantages, the details of which have been reviewed in detail by Lowenstine (2003).…”

Section: Introductionmentioning

confidence: 99%

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Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Foster

2005

Toxicol Pathol

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This review focuses on the background hepatic pathology present in three of the most commonly used species in the safety assessment of drugs, namely the beagle dog, the marmoset and the cynomolgus macaque. Both the nonneoplastic and neoplastic pathology are reviewed with a discussion on the potential impact that significant background pathology might have on the interpretation of any drug-induced pathology during subsequent testing. Although specific instances, such as parasitological infection in wild-caught primates can pose problems of interpretation, in general the background pathology in both the dog and the nonhuman primates, is not significantly different from that seen in the liver of laboratory rodents and with experience should not pose significant problems for the experienced pathologist. The relative merits of the primate versus the dog as a choice of second species are also considered in some detail. Although there is an inbuilt prejudice that the primate will more closely mimic subsequent effects that might occur in man in the clinic, insofar as the liver is concerned, there are many instances where the dog has been more representative of human exposure and metabolism and there is little evidence to show that the nonhuman primate is consistently better than dog in predicting human liver toxicity. As with most areas of science, comparative toxicology would dictate that the more information gained, from as wide a range of species as is practical, will give the best assessment for any subsequent problems in the clinic. This pragmatic approach should prove to be more successful than one based entirely upon an assumption, and in many cases the assumption is incorrect, that the primate always predicts human toxicity better than the nonprimate, including the dog.

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Section: Drug-induced Nonneoplastic Hepatic Changesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Foster

2005

Toxicol Pathol

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“…For instance, dogs are an important nonrodent species used in scaling pharmacokinetics and evaluating toxicology in drug development research. Yet, several notable differences have been described in the ligand selectivity and expression levels of human P450s and their canine homologs (Eguchi et al, 1996;Tibbitts, 2003). As a patient population, dogs are also increasingly being considered by pharmaceutical companies (Petkewich, 2007).…”

mentioning

confidence: 99%

Evaluation ofEscherichia coliMembrane Preparations of Canine CYP1A1, 2B11, 2C21, 2C41, 2D15, 3A12, and 3A26 with Coexpressed Canine Cytochrome P450 Reductase

Locuson¹,

Ethell²,

Voice³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The preparation of bacterial membranes ("Bactosomes") containing expressed canine (beagle) hepatic cytochromes P450 (P450s) is described. cDNAs from seven canine P450s were subcloned into inducible expression plasmids and, for the first time, cotransformed and expressed with a canine P450 oxidoreductase in Escherichia coli to produce active, full-length, native sequence P450s. Enzyme expression levels, although variable, were generally sufficient to enable short incubation times and to limit the total protein present in enzyme incubations. Steady-state kinetics of CYP1A1, 2C21, and 2D15 Bactosomes demonstrated similarities with dog liver microsomes or Baculosomes. However, 3A12 lacked substrate inhibition in the formation of 1-OH midazolam, and 2B11 displayed non-Michaelis-Menten kinetics, suggesting possible differences in protein interaction effects. In monitoring the metabolites of common P450 substrates, phenacetin deethylation, temazepam demethylation, and bufuralol 1-hydroxylation were shown to be relatively selective reactions catalyzed by CYP1A1, 2B11, and 2D15, respectively. 1-OH midazolam was formed in higher quantities by CYP2B11 and 2C21 than by 3A12, raising questions about the use of midazolam as a CYP3A12 probe in vivo. In summary, a panel of recombinant P450s was produced to make up for the lack of commercially available canine P450 isoforms. The Bactosomes are expected to facilitate reaction phenotyping and metabolic drug-drug interaction assessment in canine drug development and to enable the study of interspecies differences in P450-mediated drug metabolism.

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“…However, this does not rule out the potential for uptake-mediated clearance of MRK-1, and there are no data available on the in vivo clearance pathways for M1 and M2. The lack of conversion of M1 to M2 in dog hepatocytes was consistent with known N-acetylation species differences (Tibbitts, 2003;Gao et al, 2006;Loureiro et al, 2013). Further qualification of the PK model using rat data would therefore clearly have been desirable; however, the metabolism of M1 to M2 observed in rat blood, but not in dog or human blood, rendered such a validation questionable both in terms of feasibility and value.…”

Section: Discussionmentioning

confidence: 90%

A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose

Martin

Hill

Baker

et al. 2016

Drug Metabolism and Disposition

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A preclinical drug candidate, MRK-1 (Merck candidate drug parent compound), was found to elicit tumor regression in a mouse xenograft model. Analysis of samples from these studies revealed significant levels of two circulating metabolites, whose identities were confirmed by comparison with authentic standards using liquid chromatography-tandem mass spectrometry. These metabolites were found to have an in vitro potency similar to that of MRK-1 against the pharmacological target and were therefore thought to contribute to the observed efficacy. To predict this contribution in humans, a pharmacokinetic (PK) modeling approach was developed. At the mouse efficacious dose, the areas under the plasma concentration time curves (AUCs) of the active metabolites were normalized by their in vitro potency compared with MRK-1. These normalized metabolite AUCs were added to that of MRK-1 to yield a composite efficacious unbound AUC, expressed as "parent drug equivalents," which was used as the target AUC for predictions of the human efficacious dose. In vitro and preclinical PK studies afforded predictions of the PK of MRK-1 and the two active metabolites in human as well as the relative pathway flux to each metabolite. These were used to construct a PK model

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Issues Related to the Use of Canines in Toxicologic Pathology—Issues With Pharmacokinetics and Metabolism

Cited by 35 publications

References 45 publications

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Spontaneous and Drug-Induced Hepatic Pathology of the Laboratory Beagle Dog, the Cynomolgus Macaque and the Marmoset

Evaluation ofEscherichia coliMembrane Preparations of Canine CYP1A1, 2B11, 2C21, 2C41, 2D15, 3A12, and 3A26 with Coexpressed Canine Cytochrome P450 Reductase

A Pharmacokinetic Modeling Approach to Predict the Contribution of Active Metabolites to Human Efficacious Dose

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