Cytochrome P450 and Its Role in Veterinary Drug Interactions

Trepanier, Lauren A.

doi:10.1016/j.cvsm.2006.05.003

Cited by 34 publications

(27 citation statements)

References 59 publications

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“…In contrast, we found higher mRNA levels for CYP2D15 than for CYP3A26 in dog liver, which supports previous reports showing that CYP2D15 protein represents ϳ20% of total P450 liver content (Sakamoto et al, 1995), whereas CYP3A represents ϳ14% (Eguchi et al, 1996). Despite differences in CYP2D expression between human and dog, similar oxygenation kinetics were observed with the respective liver microsomes (Bogaards et al, 2000;Trepanier, 2006). Comparing the oxidation of CYP2D6 substrates in various preclinical species including mouse, rat, rabbit, dog, micropig, and monkey, the kinetics of human CYP2D6 were most similar to those of the canine ortholog CYP2D15 (Bogaards et al, 2000), which suggests the dog model is a better predictor of human CYP2D-mediated metabolism than other preclinical species.…”

Section: Discussionsupporting

confidence: 39%

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Haller¹,

Schuler²,

Lazic³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Beagle dogs are widely used in preclinical pharmacokinetic, safety, and formulation studies. However, little is known about intestinal and hepatic distribution of major enzymes and transporters involved in oral absorption and presystemic drug metabolism. We characterized mRNA levels of CYP3A12, CYP3A26, CYP2D15, UGT1A6, ABCB1 (MDR1), ABCC1 (MRP1), ABCG2 (BCRP), SLC15A1 (PEPT1), and SLC22A1 (OCT1) in dog liver and along the intestine by real-time quantitative reverse transcription-polymerase chain reaction. Tissue protein levels of CYP2D15, MDR1, and PEPT1 were obtained by Western blot. Gene distribution and expression variability was statistically described by a generalized additive mixed model smoothing function and correspondence analysis. Results were compared with the expression pattern known for the human orthologs. Hepatic mRNA levels for metabolic enzymes were generally higher than those for membrane transporters, whereas in the intestine the opposite was observed. Hepatic mRNA levels followed the order CYP2D15 > UGT1A6 Ϸ CYP3A26 > ABCB1 Ϸ SLC15A1 Ϸ SLC22A1 > ABCG2 > ABCC1 Ϸ CYP3A12. Along the gut, the genes were differentially distributed with greatest expression in duodenum/upper jejunum (ABCG2), middle jejunum (ABCB1 and SLC15A1), or in cecum/colon (ABCC1 and CYP2D15). CYP3A12, CYP3A26, SLC22A1, and UGT1A6 had a rather uniform expression. Intestinal mRNA profiles of CYP2D15, ABCB1, and SLC15A1 correlated with the respective protein levels. Canine CYP3A12/26, CYP2D15, and ABCB1 colonic distributions differed from those of human orthologs, whereas UGT1A6, ABCC1, ABCG2, SLC15A1, and SLC22A1 were comparable to those of humans in both small and large intestine. We aim to apply these data to better interpret pharmacokinetic studies in dogs with respect to their human relevance.

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Section: Discussionsupporting

confidence: 39%

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Haller¹,

Schuler²,

Lazic³

et al. 2012

Drug Metab Dispos

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“…Only propofol, ondansetron, ketoconazole, cyclosporin, vincristine, clomipramine, diazepam, fluoxetine, and loperamide possessed low micromolar or nanomolar IC 50 s. The DDI potential of some of these compounds was briefly reviewed (Trepanier, 2006). Except for propofol, which was confirmed to be a CYP2B11 substrate (Hay Kraus et al, 2000), several of the compounds listed above may be administered for at least several days.…”

Section: Canine P450 Inhibition By Veterinary Medicinesmentioning

confidence: 99%

In Vitro Drug-Drug Interaction Screens for Canine Veterinary Medicines: Evaluation of Cytochrome P450 Reversible Inhibition

Aidasani

Zaya²,

Malpas³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Little information regarding the metabolic pathways of pharmaceutical agents administered to dogs, or the inhibition of those metabolic pathways, is available. Without this information, it is difficult to assess how combinations of drugs, whether new or old or approved or nonapproved, may increase the risk for metabolic drug-drug interactions in dogs. Because mammalian xenobiotic metabolism pathways often involve the hepatic cytochrome P450 (P450) monooxgenases, canine liver microsome P450 inhibition screens were tested to evaluate the potential metabolic drug interaction risk of commonly used veterinary medicines. A probe substrate cocktail was developed for four of the five major hepatic canine P450s and used to evaluate their inhibition by 45 canine therapeutic agents in a single-point IC 50 screen. Moderate inhibitors (>25%) were further characterized with an automated ninepoint IC 50 assay that identified ketoconazole, clomipramine, and loperamide as submicromolar CYP2D15 inhibitors. Additional inhibitors belonged to the antiemetic, antimitotic, and anxiolytic therapeutic classes. According to the marker activities, the relative frequency of P450 inhibition by isoform followed the sequence CYP2D15 > CYP2B11 > CYP2C21/41 > CYP3A12/26 > CYP1A1/2. The findings presented suggest there is some overlap in canine and human P450 inhibition specificity. However, occasional differences may give human drugs used off-label in dogs unexpected P450 inhibition profiles and, therefore, cause an unexpected drugdrug interaction risk.The number of reports describing the basic enzymology of drugmetabolizing enzymes in nonhuman species has increased the last decade. Notable examples include the characterization of several homologs of the major human xenobiotic-metabolizing cytochromes P450 that were cloned from canine hepatocytes (Roussel et al., 1998;Shou et al., 2003). Single nucleotide polymorphisms within canine P450s that alter activity have also been identified, as have P450 isoforms that appear to only be expressed in a fraction of the beagle population (Sakamoto et al., 1995;Blaisdell et al., 1998). More recently, three hepatic feline P450s cDNAs were characterized, two of which were expressed and characterized (Tanaka et al., 2005(Tanaka et al., , 2006. Whereas some of these reports bring a better understanding of when metabolism in preclinical species may or may not reflect the human situation (Martignoni et al., 2006;Turpeinen et al., 2007), there have been few reports on how specific P450s are inhibited by or metabolize pharmaceuticals used in the animal health field.For instance, in the development of new therapies for dogs, prediction of whether concomitant medications in the patient population may inhibit metabolic clearance pathways would be helpful in the assessment of the metabolic drug-drug interaction (DDI) potential. However, there is a lack of canine P450 inhibition data and understanding of basic canine enzymology that has caused in vitro canine drug interaction assessment to lag behind that of h...

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“…Accordingly, the cat is considered the most sensitive domestic species to the haematological effects of the antibiotic (Watson, 1980). Prolongation of the anaesthetic effects of pentobarbital and other compounds have been reported in therapeutically treated cats (Trepanier, 2006).…”

Section: Companion Animalsmentioning

confidence: 99%

Scientific Opinion on Chloramphenicol in food and feed

2014

EFS2

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Chloramphenicol is an antibiotic not authorised for use in food-producing animals in the European Union (EU). However, being produced by soil bacteria, it may occur in plants. The European Commission asked EFSA for a scientific opinion on the risks to human and animal health related to the presence of chloramphenicol in food and feed and whether a reference point for action (RPA) of 0.3 µg/kg is adequate to protect public and animal health. Data on occurrence of chloramphenicol in food extracted from the national residue monitoring plan results and from the Rapid Alert System for Food and Feed (RASFF) were too limited to carry out a reliable human dietary exposure assessment. Instead, human dietary exposure was calculated for a scenario in which chloramphenicol is present at 0.3 µg/kg in all foods of animal origin, foods containing enzyme preparations and foods which may be contaminated naturally. The mean chronic dietary exposure for this worst-case scenario would range from 11 to 17 and 2.2 to 4.0 ng/kg b.w. per day for toddlers and adults, respectively. The potential dietary exposure of livestock to chloramphenicol was estimated to be below 1 µg/kg b.w. per day. Chloramphenicol is implicated in the generation of aplastic anaemia in humans and causes reproductive/hepatotoxic effects in animals. Margins of exposure for these effects were calculated at 2.4 × 10 5 or greater and the CONTAM Panel concluded that it is unlikely that exposure to food contaminated with chloramphenicol at or below 0.3 µg/kg is a health concern for aplastic anaemia or reproductive/hepatotoxic effects. Chloramphenicol exhibits genotoxicity but, owing to the lack of data, the risk of carcinogenicity cannot be assessed. The SUMMARYChloramphenicol is a broad-spectrum antibiotic effective against Gram-positive and Gram-negative bacteria and, in the past, has been widely used to treat infections in both humans and animals. Chloramphenicol is not authorised for use in food-producing animals in the European Union (EU) but may be used in human medicine and in treatments for non-food-producing animals. Apart from its potential occurrence as a residue in food from illicit treatment of food-producing animals, chloramphenicol has also been used in feed and food enzyme products and may occur naturally in plants from its production by the soil bacterium Streptomyces venezuelae.The EFSA Scientific Opinion entitled "Guidance on methodological principles and scientific methods to be taken into account when establishing Reference Points for Action (RPAs) for non-allowed pharmacologically active substances present in food of animal origin" identified an approach for establishing RPAs for various categories of non-allowed pharmacologically active substances. However, the opinion also identified certain categories of non-allowed pharmacologically active substances that are considered to be outside the scope of the procedure, including substances causing blood dyscrasias (aplastic anaemia) such as chloramphenicol. As chloramphenicol is excluded fro...

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Cytochrome P450 and Its Role in Veterinary Drug Interactions

Cited by 34 publications

References 59 publications

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

Expression Profiles of Metabolic Enzymes and Drug Transporters in the Liver and along the Intestine of Beagle Dogs

In Vitro Drug-Drug Interaction Screens for Canine Veterinary Medicines: Evaluation of Cytochrome P450 Reversible Inhibition

Scientific Opinion on Chloramphenicol in food and feed

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