Year: 2019 | Volume: 1 | Issue: 1 | Page No.: 1-8
Recieved: December 09, 2019 Accepted: December 11, 2019 Published: December 31, 2019
Comparison of Cytochrome P450-Mediated Drug Metabolism in Cats and Dogs
Theophylline (THP), Phenytoin (PHT), Metoprolol (MTP) and Quinidine (QUN) were intravenously administrated to cats and dogs in order to compare the pharmacokinetic parameters between both species. Dose of THP 5 mg/Kg to cats and dogs, PHT 1 mg/Kg to cats and 5 mg/kg to dogs, MTP and QUN 2 mg/Kg to cats and dogs were intravenously injected to the animals with a washout period of 4-6 weeks. A high performance liquid chromatography method was used to determine plasma concentrations. Plasma concentrations plotted against time on semilogarithmic coordinates indicated that pharmacokinetics of all the four drugs best fitted to 1-compartment open model. Total body clearance (Cltot) of PHT in cats was much smaller (1/26) than dogs with quite long elimination half-life (102 ± 17 hr), suggesting that CYP2C activities of cats are extremely low. This suggests that CYP2C substrate should be carefully administrated to cat. The Cltot of QUN in cats was 4-folds higher than dogs. While MTP substrate of CYP2D demonstrated similar activity to that of dogs. THP pharmacokinetics showed moderate activities in cat but compared with dog THP was slightly small in cats. These results suggest that CYP1A substrate should be prescribed similar to dogs and CYP3A in cats using different dosage regimen than dogs.
Comparison, CYP450, Drug metabolism, Cats, Dogs
TO CITE THIS ARTICLE
Syed Sher Shah Sadaat , Farid Ahmad Tanin , Abdul Razaq Irshad , Amanullah Aziz and Kazuki Sasaki
2019. Comparison of Cytochrome P450-Mediated Drug Metabolism in Cats and Dogs. Journal of Clinical Pharmacology and Medical Research, 1: 1-8
Phase one oxidation is one of the most important pathways of drug metabolism. Attention is usually focused on oxidation mediated by the microsomal mixed function oxidase system Cytochrome P450 (CYP450) due to its central role and significance in governing the biotransformation of many drugs and xenobiotics. An understanding of this pathway is often critical to make interspecies extrapolations. It is well known that large differences in enzyme expression and function are existed between species. Among the reactions catalyzed by drug metabolizing isoenzymes in the hepatic endoplasmic reticulum, CYP450 isthe most intensively studiedsystem, including in cats , in dogs ,
in Chicken , in cattle  and in humans . Many drugs, which are metabolized by CYP450 isoenzymes, have been used in treatment of feline and canine diseases. In addition, prescribing drugs in extra label manner, is not rare in cats and dogs, because approved drugs are limited for these two species. The information on CYP450 isoenzymes activities are, therefore, quite important in feline and canine species clinics.
Previous in vitro studies indicated that Tolbutamide hydroxylation (TBH) activity was negligible in hepatic microsomes ofboth male and female cats,suggesting CYP2C activities in cats areextremelylow . This suggests that CYP2C substrates should be carefully administrated to cats. It was confirmed that CYP2D activities were higher (3-folds), but CYP3A activities were lower (one-fifth) in female cats. These results might suggest that CYP2D and 3A substrates should be prescribed for male and female cats using different dosage regimens .
Differences in biotransformation rates and reactions are the major factors in determining species differences in drug action and kinetics. Therefore, it is very important to know drug pharmacokinetic parameters in the cats and dogs to avoid undesirable drug-drug interaction and prevent accumulation and toxicity of the drug. However, very little is known about CYPs activities in feline compared with other mammalian species . Alternatively, in cat only few isozymes are separately studied . Furthermore, to our knowledge up to date pharmacokinetic parameters between feline and canine are rarely studied. Thus, these encourage us to evaluate pharmacokinetics as a comparison between feline and canine species. In this study, therefore, we examined pharmacokinetics of THP, PHT, MTP and QUN as a selected four marker substrates that were used previously in other animal species THP , PHT , MTP  and QUN  for CYP1A, 2C, 2D and 3A, respectively to characterize CYP activities in cats and compare with those of dogs.
2. MATERIALS AND METHODS
2.1. Drugs and chemicals
Theophylline and 7-β-hydroxypropyltheophylline were obtained from Sigma chemical company (St. Louis, MO, USA). Phenytoin, 5-(-p-methylphenyl)-5-phenylhydantoin, quinidine sulfate and metoprolol tartrate powder were purchased from Wako pure chemical industries limited (Osaka, Japan). All other chemicals used as reagents were of the highest purity analytical or HPLC grade.
Five female short hair cats (1.5-years, weighing from 2.2 to 3.5 Kg) were bought from Iffa credo (France). Five beagle dogs (1.5-years, weighing from 11 to 14 Kg) were purchased from CSK Research Park Co. Ltd (Nagano, Japan). The cats and dogs were housed in stainless-steel and metallic cages individually with a 12-hr light/dark cycle. Stable temperature and relative humidity were maintained at 19-22oC and 40 to 70%, respectively. The cats were given food (Science diet, feline maintenance, Hill’s pet nutrition, Topeca, KS, USA) once a day and accessed to water ad libitum. The dogs were provided water ad libitum and pelleted dry food (one Lac Meal®; Morinyu Sun World, Tokyo, Japan) once a day.
The cats and dogs were handled according to the guidelines for the care and use of laboratory animals, Faculty of Agriculture, Tokyo University of Agriculture and Technology. They did not receive drug or feed additives before experiments.
2.3. Study design
The pharmacokinetics of THP, PHT, MTP and QUN were examined in clinically healthy cats and dogs by in vivo tests. THP, PHT, MTP and QUN were used as selected marker probes for CYP1A, 2C, 2D and 3A subfamilies, respectively.
The THP, PHT, MTP and QUN were intravenously injected, dose of THP 5 mg/Kg to cats and dogs, PHT 1 mg/Kg to cats and 5 mg/Kg to dogs, MTP and QUN 2 mg/Kg to cats and dogs, respectively into the left cephalic vein in both cats and dogs. The injected solutions were prepared by dissolving THP, PHT and MTP in D/W except for the QUN that was first dissolved in 1.5 mL ethanol and then the final volume was adjusted to 50 mL by adding sterilized distilled water to yield 5 mg/mL. The pH of the solution for THP was adjusted at 8-9 by 2 N NaOH.The final concentrations were adjusted to 20 mg/mL for THP, 5 mg/mL for PHT, 10 mg/mL for MTP and 5 mg/mL for QUN, respectively by adding sterilized distilled water. After THP, PHT, MTP and QUN administration, blood samples (1.5 mL) for cats and (3 mL) for dogs were collected in glass test tubes containing Na2 EDTA from the right cephalic vein as follows: at 0.5, 1, 2, 4, 6, 8, 12, 24 and 34 hr for THP in cats, 0.5, 1, 2, 4, 6, 8 and 12 hr for THP in dogs, 1, 9, 24, 48, 72, 96, 120,144, 168, 216, 288, 360, 432 and 504 hr for PHT in cats and 1. 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr for PHT in dogs 0.5, 1, 2, 3, 4 and 6 hr for MTP in cats and 1, 2, 3, 4, 6, 8 hr for MTP in dogs, 0.5, 1, 2, 3, 4, 6, and 8 hr for QUN in cats and, 0.5, 1, 2, 3, 4, 6, 8, 10 and 12 hr for QUN in dogs, respectively. The heparinized plasma, used to determine the plasma concentrations of the four drugs, was separated by centrifugation (1500 g, 5 min) at 4°C and frozen at –20°C until assay. Eight experiments were conducted at eight different occasions with a washout period of 4-6 weeks between the experiments. One day before the start of each experiment, blood samples were taken from each cat and dog. The samples were examined for interfering peaks in the plasma, if any.
2.4. Determination of plasma THP concentrations
Plasma THP concentrations were determined by use of HPLC method described by Saitoh et al.  . After thawing, 0.2 mL of plasma for cat and 0.5 mL for dog were spiked with 0.1 mL solution of internal standard (7-β-hydroxypropyltheophylline, 100 μg/mL for cats and 200 μg/mL for dogs). The samples were extracted with 5 mL of a mixture of chloroform and 2-propanol (85:15%, v/v). After 1 min vortex, the mixture was centrifuged at 1600 g for 5 min. The upper foam was completely aspired. The organic layer was transferred to a clean pear-shaped evaporating flask. Evaporation was performed at 40°C to dryness under a reduced pressure using a rotary evaporator (Rota vapor® R-114, Shibata Scientific Technology Ltd. Tokyo, Japan). The residue was reconstituted in 0.5 mL mobile phase for cats and 1 mL for dogs. After filtration with 0.45-μm filter, 50 μL of the filtrate was injected into HPLC column for cat samples [Mighty sil; RP-18GP 250-3.0 (5 μm) Cica-Reagent], Kanto Chemical CO. INC., Tokyo, Japan) and for dogs samples (TSK gel® ODS-120T, 5 μm particle size, 250 mm x 4.6 mm i.d,; TOSOH co., Tokyo, Japan). Column effluent was monitored at 254nm wavelengths using an ultraviolet detector (SPD-6A); Shimadzu Corporation, (Kyoto, Japan). The mobile phase was a mixture of acetonitrile and distilled water (10:90, v/v). The pH of mobile phase was adjusted at 3 with 7 M phosphoric acid. The solvent was delivered at flow rate of 0.6 mL/min. The detection limit (LOD) was 60 ng/mL at a signal-to-noise ratio of 3. The recoveries of THP and 7-β were 79.5 ± 3.9% (CV = 5%) and 79.6 ± 4.4% (CV = 6%) at 2 μg/ mL and 20 μg/mL in cats samples and 90.1 ± 1.8% (CV = 6.1%) in dog samples at 10 μg/mL, respectively. The intra-day CV values were 2.6 and 3.5% at 0.2 and 2 μg/mL for cats and 1.8 and 2.0% at 1 and 10 μg/mL for dogs , respectively (cat, n = 5 and dog, n = 5). The inter-day CV values were ranged from 3.1% to 3.5% at 0.2 μg/mL and 5.1 to 8.8% at 2 μg/mL in cat samples and 2.1 to 4.8% at 1 μg/mL and 1.9 to 6.1% at 10 μg/mL in dog samples (3 days, 5 determinations per day in cat and dog samples), respectively.
2.5. Determination of plasma PHT concentrations
Phenytoin plasma concentration was determined byuse of HPLC with UV spectrophotometric detector method described by Tanaka et al. . 5-(-p-methylphenyl)-5-phenylhydantoin was used as an internal standard. After thawing, 0.2 mL plasma for cat and 0.1 mL for dog samples were mixed with 0.1 mL of internal standard containing (10 μg/mL) of 5-(p-methylphenyl)-5-phenylhydantoin (5-P). The samples were deproteinized with 50 μL, (0.2 M HCL) and then extracted with 3 mL dichloromethane and N-Pentane (1:1, v/v). The mixture was centrifuged at 1600 g for 5 minandthen the upper organic layer was transferred to a clean pear-shaped evaporating flask. Evaporation was performed at 40°C to dryness under a reduced pressure using a rotary evaporator (Rota vapor® R-114, Shibata Scientific Technology Ltd. Tokyo, Japan). The residue was reconstituted in a 0.5 mL mobile phase for cat samples and 0.1 mL for dog samples. After filtration with 0.45-μm filter, 50 μL of the filtrate was injected into HPLC column (RP-18 GP 250-3.0, 5 μm, Kanto Chemical CO. INC., Tokyo, Japan) for cats samples and (TSK gel® ODS-120T, 5 μm particle size, 250 mm x 4.6 mm i.d,; TOSOH CO., Tokyo, Japan) for dog samples. Column effluent was monitored at 215 nm wavelengths using an ultraviolet detector (SPD-6A); Shimadzu Corporation, (Kyoto, Japan). The mobile phase was a mixture of 50 mM sodium hydrogen phosphate buffer and acetonitrile (69:31, v/v). The pH of the mobile phase was adjusted at 5 with 7 M phosphoric acid. The solvent was delivered at a flow rate of 0.6 mL/min in cat samples and 1 mL/min in dog samples. The recoveries of PHT and 5-P were 92.1 ± 3.2% (CV = 3.6%) at 2 μg/mL and 93.8 ± 3.2 % (CV = 3.4%) at 20 μg/mL for cats and 93.8 ± 9.8 (CV = 10.4%) at 1 μg/mL for dogs samples,respectively. The intra-day CV values were 1 and 2.8% at 0.2 and 2 μg/mL (n = 5) for cats and 9.2 to 10.4% at 0.1 and 1 μg/mL (n = 5 ) for dogs, respectively. The inter-day CV values were ranged from 1.0% to 3.6% at 0.2 μg/mL and 1.6% to 4.5% at 2 μg/mL for cats and 9.3% to 10.5% at 0.1 and 9.1% to 9.8% 1μg/mL in dogs, respectively (3 days, 5 determinations per day in cat and dogs).
2.6. Determination of plasma MTP concentrations
Plasma metoprolol concentrations were examined by use of HPLC with a fluorometric detector (RF-535; Shimadazu Corporation). After thawing, 0.2 mL of plasma was spiked with 0.8 mL of acetonitrile. The mixture was centrifuged at 12000 g for 3 min. The organic layer was transferred into a clean pear-shaped evaporating flask. Evaporation was performed at 40°C to dryness under a reduced pressure using a rotary evaporator (Rota vapor® R-114, Shibata Scientific Technology Ltd. Tokyo, Japan). The residue was reconstituted in 0.2 mL of mobile phase. After filtration with 0.45-μm filter, 50 μL of the filtrate was injected into a HPLC column [RP-18 GP 250-3.0, (5μm), Kanto Chemical CO. INC., Tokyo, Japan]. Column effluent was monitored by fluorescence detector with EX and EM wavelengths set at 225 nm and 320 nm, respectively. The mobile phase was a mixture of 0.1 mM 1-Hepatane sulfonic acid, 1% acetic acid solution with 15% of acetonitrile at (85:15, v/v). The mobile phase was pumped at the flow rate of 1 mL/min. The recoveries of MTP were 81 ± 4% (CV = 5%) and 83.6 ± 5% (CV = 6%) at 0.2 μg/mL for cats and dogs, respectively.The intra-day CV values were 4.0% and 4.1% for cats at 0.02 μg/mL and 0.2 μg/mL, respectively and 6.1% and 7.2% for dogs, respectively at 0.02 and 0.2 μg/mL (n = 5). The inter-day CV values were ranged from 2.5 to 7.4% and 4.1 to 4.5% for cats and for dog’s samples 5.1 to 5.9% and 6.0 to 7.3% (3 days, 5 determinations per day), at 0.02 and 0.2 μg/mL, respectively.
2.7. Determination of plasma QUN concentrations
Plasma QUN concentrations were determined by use of HPLC with a fluorometric detector (RF-535; Shimadazu Corporation) as described by Edstein et al.  with slight modifications. After thawing, 0.2 mL, plasma for cat and 0.25 mL for dog were spiked with 0.8 mL acetonitrile in cat samples and 0.75 mL in dog samples. The mixture was vortexed for a few seconds and centrifuged (16000 g, 3 min). 0.5 mL of the supernatant was transferred into a clean pear-shaped flask. Evaporation was done at 40°C to dryness under a reduced pressure using a rotary evaporator (Rota vapor® R-114, Shibata Scientific Technology Ltd. Tokyo, Japan). The residue was reconstituted in 0.5 mL mobile phase. After filtration with 0.45-μm filter, 50 μL of the filtrate was injected into a HPLC column [RP-8 GP 250-4.6 (5μm), Kanto Chemical CO. INC., Tokyo, Japan]. The EX and EM wave lengths were 340 nm and 425 nm, respectively. The mobile phase was a mixture of 0.4% triethylamine (pH 2.5 adjusted with 7 M phosphoric acid) and acetonitrile (88:12, v/v). The flow rate was 1 mL/min. The detection limit was 1 ng/mL at a signal to-noise ratio of 3. The recoveries were 97.7 ± 3.4% (n = 5) at 1 μg/mL and 99.1 ± 8.5% (n= 5) at 0.25 μg/mL for cat and dog, respectively. The intra-day CV values were 2.8 and 3.0% at 0.1 and 1 μg/mL for cats and 3.7 and 8.5% for dog’s samples at 0.02 and 0.25 μg/mL, respectively. The inter-day CV values were ranged from 2.2 to 3.4% and 1.9 to 3.5% at 0.1 and 1 μg/mL for cats and 2.0 to 7.9% for dogs at 0.02 and 0.25 μg/mL, respectively (3 days, 5 determinations per day).
2.8. Pharmacokinetic analysis
Plasma concentration-time curves after THP, PHT, MTP or QUN injections were fitted to the following monoexponential equation for both cat and dog using the nonlinear fitting program, MULTI .
Where, Cp(0), Kel and t represent plasma concentration at time 0 hr, elimination rate constant and time, respectively. The area under the plasma concentration-time curve (AUC) from time 0 to the last sampling time was calculated by trapezoidal method. AUC from the last sampling time to infinity was calculated by integrating theoretical equation. The elimination half-life (t1/2), apparent volume of distribution (Vd), mean residence time (MRT) and total body clearance (Cltot) were calculated using the following equations.
Where, AUMC is the first moment curve for the relation between plasma concentrations and time.
Data was analyzed by unpaired, two- tailed Student’s t-test, the difference between cats and dogs were considered significant when P < 0.05.
3.1. Plasma pharmacokinetics
After intravenous bolus injection, the plasma concentration-time curves of each drug declined monoexponentially in both cats and dogs, which were characteristic of one-compartment open model as shown in (Fig. 1 and 2).
Pharmacokinetic parameters of THP, PHT, MTP and QUN from five cats and five dogs are summarized in Table 1.
Each value is represented by mean ± SD (n = 5 for cats and n = 5 for dogs). The initial data for C0 and Kel were estimated using a nonlinear least square fitting program. Pharmacokinetic parameters including t1/2, Vd, Cltot and MRT were calculated using conventional methods. AUC0-inf was calculated by integrating theoretical equation. Superscripts indicate significant differences between values with the same superscript (P < 0.05).
Estimated t1/2 and MRT values for PHT (CYP2C substrate) were extremely longer (30-folds) in cats than in dogs. The value for AUC was also significantly higher (6-folds) in cats than in dogs. In contrast, value for Kel was significantly lower (1/30) in cats than that in dogs. Whereas both animal species show similar values for Vd. Clearance total (Cltot) of PHT was much lower (1/30) in cats than in dogs. In contrast, for QUN (CYP3A substrate) cats indicated significantly short t1/2 and MRT (one-half) than dogs. The value for AUC was also significantly lower (1/4) in cats than that in dogs. On the contrary, the values for Kel and Vd were significantly higher (2-folds) in cats than that in dogs. The Cltot of QUN was significantly higher (4-folds) in cats than that in dogs. Estimated t1/2 and MRT values for THP were significantly longer (2-folds) in cats than in dogs. The Vd value was slightly higher in cats than that in dogs, the values were significant when P<0.05. In contrast, cats showed significantly low Kel (less than a half) than dogs. Cltot of THP (CYP1A substrate) was slightly smaller in cats than in dogs. Pharmacokinetic parameters of MTP did not show any significant difference between cats and dogs.
Plasma concentration time-curve profiles of intravenous (a) theophylline (THP) and (b) Phenytoin (PHT) in cats and dogs. THP was administrated at 5 mg/Kg to cats and dogs. PHT was administrated at 1 mg/Kg to cats or 5 mg/Kg to dogs, closed and open circles represent observed values from five cats and five dogs, respectively. Each point and vertical line represents a mean ± SD (n = 5, cats and 5 dogs).
Plasma concentration time-curve profiles of intravenous (a) metoprolol (MTP) and (b) Quinidine (QUN) in cats and dogs. MTP and QUN were administrated at 2 mg/Kg to cats and dogs, open and closed circles represent observed values from five cats and five dogs, respectively. Each point and vertical line represents mean ± SD (n = 5, cats and 5 dogs).
Pharmacokinetic parameters of THP (5 mg/Kg), PHT (1 mg/Kg) for cats and (5 mg/Kg) for dogs, MTP (2 mg/Kg) and QUN (2 mg/Kg) following i.v. injection between cats and dogs
In this study, pharmacokinetics of THP, PHT, MTP and QUN as substrates for CYP1A, 2C, 2D and 3A subfamilies were evaluated in cats and in dogs. As a result, it is demonstrated that cats have extremely low Cltot of PHT compared with dogs, suggesting that CYP2C activities are extremely low in cats. In contrast, it is demonstrated that Cltot of QUN was higher in cats compared to that in dogs, suggesting that CYP3A activities are higher in cats than indogs. In a study by Shah et al. , it is demonstrated that TBH (CYP2C substrate) activities are extremely low in cats. In this study, we confirmed that PHT elimination was extremely low in cats compared with dogs. However, it is well known that PHT is metabolized to its phenyl metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) by CYP2C9 and 2C19 in humans and rats as described by Veronese et al., Bajpai et al.  and Cuttle et al. . Based on Cltot, PHT activities were found to be (1/30) of dogs in the present study. However, a similar results with the previously studies were described by Kamali et al.  who reported that activities of PHT-4-hydroxylation in cat is extremely low compared with rats (1/650) and humans (1/25). Additionally, there are some reports supporting this suggestion. Hassell, et al.  found limited PHT hydroxylation determines the fate of orally administered PHT in the cats in contrast to humans. Results of this study are consistent with Kamali et al.  .The extremely low Cltot resulted in a long half-life in the cats. Consequently, in vitro and in vivo studies are in a good agreement. It is therefore, suggested that cats have extremely low activities of CYP2C compared with other animal species.
Based on Cltot, there were significantly higher activities for QUN metabolism (4-folds) in cats, compared with dogs. The greater clearance resulted in a shorter t1/2 in cat. The present in vivodata is not agreed with the previous in vitro results of cats conducted by Shah et al. , where midazolam hydroxylation activities of cats were lower than dogs. The reasons for this contradiction might be that we have used different substrates with different affinities toward CYP3A isoenzyme, midazolam for in vitro and QUN for in vivotests were used. In addition, it has been reported that the liver extraction ratio for quinidine in dogs is very low . The sensitivity of organ clearance of a drug to changes in binding within blood depends on its unbound clearance. If unbound clearance is low, relative to organ blood flow, the extraction ratio (and clearance) will always be low and depends on plasma protein binding. If the extraction ratio is high, elimination becomes perfusion rate-limited and clearance will be relatively insensitive to changes in binding . In addition, it has also been reported that hepatic blood flow for cats is greater (1.87 L/hr/Kg)  compared with that reported in dogs (1.37 L/hr/Kg) . These facts might be one of the reasons for higher clearance of cats compared with thatin dogs for QUN. Although cats have lower CYP3A activities compared with dogs, further studies should be performed to clarify the real characterization of CYP3A activities in cats. The results of this study for QUN pharmacokinetics is consistent with the previously findings reported by Neff et al. . They have been reported that t1/2 values were 1.9 and 5.5 hr in cats and dogs, respectively , Vd of 2.2 L/Kg in cats . Clohisy et al.  reported 0.21 L/hr/Kg of total body clearance in dogs. These reported pharmacokinetic parameter values were comparable to those in the present study in Table 1. It is therefore, suggested that cats have higher activities for QUN CYP3A compared to that of dogs, but consider to the in vitro results in  CYP3A activities might be lower than dogs. Therefore, further study is required to clarify the characteristics of CYP3A in cats.
Based on Cltot of THP, CYP1A activities of cats were slightly smaller than dogs. These results were similar to those reported by McKiernan et al.  and Bach et al. . Elimination rate constant (kel) of THP was smaller in cats (0.09/hr) than in dogs (0.14 per hr). Similarly, reported 0.089 and 0.12/hr in cats and dogs, respectively by McKiernan et al.. This fact may suggest that cat has lower activities of CYP1A. However, Vd values werequite different between cats (1.09 L/hr/Kg) and dogs (0.75 L/hr/Kg). Elimination half-life in cats and dogs were similar to those has been reported by McKiernan et al. [20,19] , respectively. However, low level of CYP1A1 expression has been demonstrate in human liver at both the messenger RNA (mRNA) and protein levels, but this is unlikely to be significant in the hepatic metabolism of therapeutic agents [21,27] Whereas, CYP1A1 is mainly responsible for the metabolism of theophylline in the cats . The author reported that theophylline 3-methylation is believed to be catalysed by CYP1A1 in cats, based on the high Vmax and low Km seen, in contrast to other animals. Because despite their evolutionary relatedness, CYP1A1 and CYP1A2 display markedly different expression patterns whereas CYP1A2 is constitutively expressed in mammalian liver, constitutive CYP1A1 expression appears to be low and largely extrahepatic. This is why activity of CYP1A in vivo (involve CYP1A1) is much smaller compared to in vitro (involve CYP1A2).
Parameters of MTP (CYP2D substrate) showed similarity with dogs. As for dogs t1/2 (2.1 hr) and Vd (2.64 L/Kg) are consistent with those reported by Regårdh et al.  and for cats the t1/2 (1.3 hr) by Borg et al. . These results suggested CYP2D activities are similar between cats and dogs and therefore, consistent with previous in vitro study in which I demonstrated similar activities for bufuralol hydroxylation between cats and dogs .
Combining the facts shown in in vitro study and present study, the following characteristics in cats may be derived, CYP2C activities of cats are extremely low, CYP2D activities of cats are similar to dogs, CYP1A activities might be higher and CYP3A activities might be lower than dogs, but further studies are necessary.
This research was supported by Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Japan government.