| Reference | [1]. Chirality. 2015 Mar;27(3):189-93. doi: 10.1002/chir.22412. Epub 2014 Dec 12.<br />
Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.<br />
Fang ZZ(1), Wang H, Cao YF, Sun DX, Wang LX, Hong M, Huang T, Chen JX, Zeng J.<br />
Author information: (1)Department of Toxicology, School of Public Health, Tianjin Medical University, Tianjin, P.R. China.<br />
UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 μM and 31.1 μM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism.<br />
DOI: 10.1002/chir.22412 PMID: 25502512 [Indexed for MEDLINE]<br />
<br />
[2]. Am J Vet Res. 2004 Nov;65(11):1479-82. doi: 10.2460/ajvr.2004.65.1479.<br />
Pharmacokinetics of R(-) and S(+) carprofen after administration of racemic carprofen in donkeys and horses.<br />
Mealey KL(1), Matthews NS, Peck KE, Burchfield ML, Bennett BS, Taylor TS.<br />
Author information: (1)Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA 99164, USA.<br />
OBJECTIVE: To compare plasma disposition of the R(-) and S(+) enantiomers of carprofen after IV administration of a bolus dose to donkeys and horses. ANIMALS: 5 clinically normal donkeys and 3 clinically normal horses. PROCEDURE: Blood samples were collected from all animals at time 0 (before) and at 10, 15, 20, 30, and 45 minutes and 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 24, 28, 32, and 48 hours after IV administration of a bolus of carprofen (0.7 mg/kg). Plasma was analyzed in triplicate via high-performance liquid chromatography to determine the concentrations of the carprofen enantiomers. A plasma concentrationtime curve for each donkey and horse was analyzed separately to estimate noncompartmental pharmacokinetic variables. RESULTS: In donkeys and horses, the area under the plasma concentration versus time curve (AUC) was greater for the R(-) carprofen enantiomer than it was for the S(+) carprofen enantiomer. For the R(-) carprofen enantiomer, the AUC and mean residence time (MRT) were significantly less and total body clearance (CIT) was significantly greater in horses, compared with donkeys. For the S(+) carprofen enantiomer, AUC and MRT were significantly less and CIT and apparent volume of distribution at steady state were significantly greater in horses, compared with donkeys. CONCLUSIONS AND CLINICAL RELEVANCE: Results have suggested that the dosing intervals for carprofen that are used in horses may not be appropriate for use in donkeys.<br />
DOI: 10.2460/ajvr.2004.65.1479 PMID: 15566084 [Indexed for MEDLINE]<br />
<br />
[3]. Chirality. 2016 Mar;28(3):226-9. doi: 10.1002/chir.22562. Epub 2015 Dec 28.<br />
Albumin's Influence on Carprofen Enantiomers-Hymecromone Interaction.<br />
Tang M(1), Guo Y(1), Gao Y(2), Tang C(2), Dang X(1), Zhou Z(2), Sun Y(2), Wang K(1).<br />
Author information: (1)Department of Orthopaedic Surgery, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China. (2)Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.<br />
Hymecromone is an important coumarin drug, and carprofen is one of the most important nonsteroidal antiinflammatory drugs (NSAIDs). The present study aims to determine the influence of bovine serum albumin (BSA) on the carprofen-hymecromone interaction. The inhibition of carprofen enantiomers on the UDP-glucuronosyltransferase (UGT) 2B7-catalyzed glucuronidation of hymecromone was investigated in the UGTs incubation system with and without BSA. The inhibition capability of increased by 20% (P < 0.001) of (R)-carprofen after the addition of 0.5% BSA in the incubation mixture. In contrast, no significant difference was observed for the inhibition of (S)-carprofen on UGT2B7 activity in the absence or presence of 0.5% BSA in the incubation system. The Lineweaver-Burk plot showed that the intersection point was located in the vertical axis, indicating the competitive inhibition of (R)-carprofen on UGT2B7 in the incubation system with BSA, which is consistent with the inhibition kinetic type of (R)-carprofen on UGT2B7 in the incubation system without BSA. Furthermore, the second plot using the slopes from the Lineweaver-Burk versus the concentrations of (R)-carprofen showed that the fitting equation was y=39.997x+50. Using this equation, the inhibition kinetic parameter was calculated to be 1.3 μM. For (S)-carprofen, the intersection point was located in the horizontal axis in the Lineweaver-Burk plot for the incubation system with BSA, indicating the noncompetitive inhibition of (S)-carprofen on the activity of UGT2B7. The fitting plot of the second plot was y=24.6x+180, and the inhibition kinetic parameter was 7.3 μM. In conclusion, the present study gives a short summary of BSA's influence on the carprofen enantiomers-hymecromone interaction, which will guide the clinical application of carprofen and hymecromone.<br />
DOI: 10.1002/chir.22562 PMID: 26708612 [Indexed for MEDLINE]<br />
<br />
[4]. J Vet Pharmacol Ther. 2013 Aug;36(4):320-8. doi: 10.1111/jvp.12000. Epub 2012 Aug 23.<br />
Influence of oxytetracycline on carprofen pharmacodynamics and pharmacokinetics in calves.<br />
Brentnall C(1), Cheng Z, McKellar QA, Lees P.<br />
Author information: (1)Department of Veterinary Basic Sciences, The Royal Veterinary College, Hatfield, Herts, AL9 7TA, UK.<br />
A tissue cage model of inflammation in calves was used to determine the pharmacokinetic and pharmacodynamic properties of individual carprofen enantiomers, following the administration of the racemate. RS(±) carprofen was administered subcutaneously both alone and in combination with intramuscularly administered oxytetracycline in a four-period crossover study. Oxytetracycline did not influence the pharmacokinetics of R(-) and S(+) carprofen enantiomers, except for a lower maximum concentration (Cmax ) of S(+) carprofen in serum after co-administration with oxytetracycline. S(+) enantiomer means for area under the serum concentration-time curve (AUC0-96 h were 136.9 and 128.3 μg·h/mL and means for the terminal half-life (T(1/2) k10 ) were = 12.9 and 17.3 h for carprofen alone and in combination with oxytetracycline, respectively. S(+) carprofen AUC0-96 h in both carprofen treatments and T(1/2) k10 for carprofen alone were lower (P < 0.05) than R(-) carprofen values, indicating a small degree of enantioselectivity in the disposition of the enantiomers. Carprofen inhibition of serum thromboxane B2 ex vivo was small and significant only at a few sampling times, whereas in vivo exudate prostaglandin (PG)E2 synthesis inhibition was greater and achieved overall significance between 36 and 72 h (P < 0.05). Inhibition of PGE2 correlated with mean time to achieve maximum concentrations in exudate of 54 and 42 h for both carprofen treatments for R(-) and S(+) enantiomers, respectively. Carprofen reduction of zymosan-induced intradermal swelling was not statistically significant. These data provide a basis for the rational use of carprofen with oxytetracycline in calves and indicate that no alteration to carprofen dosage is required when the drugs are co-administered.<br />
DOI: 10.1111/jvp.12000 PMID: 22913421 [Indexed for MEDLINE]<br />
<br />
[5]. Schweiz Arch Tierheilkd. 2007 Aug;149(8):353-62. doi: 10.1024/0036-7281.149.8.353.<br />
The effect of carprofen on selected markers of bone metabolism in dogs with chronic osteoarthritis.<br />
Liesegang A(1), Limacher S, Sobek A.<br />
Author information: (1)Institute of Animal Nutrition, University of Zurich, Zurich, Switzerland. [email protected]<br />
The purpose of this study was to investigate the effect of the nonsteroidal anti-inflammatory drug carprofen on bone turnover and to monitor the progress of chronic osteoarthritic dogs by measuring different bone markers and radiographic evalutation of the corresponding joints. For this purpose 20 dogs of different ages and weight were devided into 2 groups. Ten dogs were assigned to Group R, treated with carprofen, and ten dogs to Group C, which had no treatment. Radiographs of the affected joints were reviewed initially and six months later at the end of the experiment. Blood was taken 8 times from each dog. Four bone markers (Osteocalcin (OC), bone-specific alkaline phosphatase (bAP), carboxyterminal telopeptide of type I collagen (ICTP), serum CrossLaps (CTX) as well as 1,25-(OH)2-Vitamin D and parathyroid hormone (PTH) were monitored for 6 months. No significant group effects on bone markers were notied. In Group R a decrease in ICTP concentrations during the first three months and a significant decrease in CTX concentrations in the first two months of the study were observed. The bone formation marker bAP revealed a significant decrease throughout the experiment. Three dogs of Group C and one dog of Group R showed osteoarthritic progression in the radiographs. The significant decrease of CTX indicates that carprofentreatment could have a retarding effect on the progression of osteoarthritis. Radiological findings suggest that carprofen may delay osteophyte formation. The monitoring of focal metabolic processes as in bone of a osteoarthrotic joint is difficult, since the bone mass is very active and metabolic processes may have an influence on the monitoring.<br />
DOI: 10.1024/0036-7281.149.8.353 PMID: 17803115 [Indexed for MEDLINE]
|
