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Topic:Liver Function

Liver function in horses encompasses a range of physiological processes essential for maintaining homeostasis. The liver is responsible for various metabolic, detoxification, and synthetic activities, including the metabolism of carbohydrates, proteins, and fats, as well as the detoxification of endogenous and exogenous substances. It also synthesizes proteins such as albumin and clotting factors, and produces bile necessary for digestion. Liver function can be assessed through biochemical tests that measure enzyme activities and metabolite levels in the blood. This page compiles peer-reviewed research studies and scholarly articles that explore the mechanisms, assessment, and clinical implications of liver function in equine health.
Effects of body condition score (BCS) on steroid- and eicosanoid-metabolizing enzyme activity in various mare tissues during winter anoestrus.
Reproduction in domestic animals = Zuchthygiene    November 8, 2017   Volume 53, Issue 2 296-303 doi: 10.1111/rda.13104
Owen M, Ferjak EN, Cavinder CA, McCarty KJ, Yankey KC, Hart CG, Burnett DD, Dinh T, Lemley CO.The objective of this study was to determine the activity of steroid- and eicosanoid-metabolizing enzymes in horses with varying BCSs. The BCSs of twenty non-pregnant, anoestrous mares were determined prior to euthanasia, and tissue samples were collected from the liver, kidney, adrenal gland, ovary and endometrium. Cytochrome P450 1A (CYP1A), 2C (CYP2C), 3A (CYP3A) and uridine 5'-diphospho-glucuronosyltransferase (UGT) activities were determined using luminogenic substrates. The MIXED procedure of SAS was used to test the effect of BCS on enzyme activity and differences between tissues. Activ...
Effect of feed deprivation on selected parameters of lipid mobilisation and hepatic function in healthy Akhal Teke horses.
Equine veterinary journal    September 1, 2017   Volume 50, Issue 1 98-103 doi: 10.1111/evj.12730
Tóth B, Auth A, Rompos L, Bakos Z.Gastrointestinal and other systemic diseases of Equidae are often characterised by partial or complete inappetence. The catabolic processes may lead to lipid mobilisation and other metabolic disturbances. Evidence from earlier studies has revealed that during feed deprivation/inappetence, the conjugation of bilirubin is reduced causing a substantial rise of the total bilirubin and its unconjugated fraction. Objective: We hypothesised that during feed deprivation, the serum concentration of free fatty acids (FFA), triglycerides (TG), blood urea nitrogen (BUN), total bilirubin (tBIL), total bile...
Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis.
Biochemistry    July 7, 2017   Volume 56, Issue 28 3632-3646 doi: 10.1021/acs.biochem.7b00446
Plapp BV, Savarimuthu BR, Ferraro DJ, Rubach JK, Brown EN, Ramaswamy S.During catalysis by liver alcohol dehydrogenase (ADH), a water bound to the catalytic zinc is replaced by the oxygen of the substrates. The mechanism might involve a pentacoordinated zinc or a double-displacement reaction with participation by a nearby glutamate residue, as suggested by studies of human ADH3, yeast ADH1, and some other tetrameric ADHs. Zinc coordination and participation of water in the enzyme mechanism were investigated by X-ray crystallography. The apoenzyme and its complex with adenosine 5'-diphosphoribose have an open protein conformation with the catalytic zinc in one pos...
A physiologically based model for tramadol pharmacokinetics in horses.
Journal of theoretical biology    June 23, 2017   Volume 429 46-51 doi: 10.1016/j.jtbi.2017.06.028
This work proposes an application of a minimal complexity physiologically based pharmacokinetic model to predict tramadol concentration vs time profiles in horses. Tramadol is an opioid analgesic also used for veterinary treatments. Researchers and medical doctors can profit from the application of mathematical models as supporting tools to optimize the pharmacological treatment of animal species. The proposed model is based on physiology but adopts the minimal compartmental architecture necessary to describe the experimental data. The model features a system of ordinary differential equations...
Comprehensive qualification and quantification of triacylglycerols with specific fatty acid chain composition in horse adipose tissue, human plasma and liver tissue.
Talanta    May 19, 2017   Volume 172 206-214 doi: 10.1016/j.talanta.2017.05.042
Guan M, Dai D, Li L, Wei J, Yang H, Li S, Zhang Y, Lin Y, Xiong S, Zhao Z.High levels of triacylglycerols (TGs) have been linked to cardiovascular disease and liver diseases. Comprehensively analyzing TGs is helpful to understand the TGs functions in these diseases. However, due to the existence of a large number of isomers TGs and the lack of commercial standards, precise analysis of individual triacylglycerol (TG) with specific fatty acid chain composition is full of challenge. In this work, ultra-performance liquid chromatography (UPLC) coupled with electrospray ionization (ESI) mass spectrometry (MS) were employed for comprehensive qualification and quantificati...
Study on the impact of liver fluke infection on the welfare of horses.
The Veterinary record    March 25, 2017   Volume 180, Issue 12 310 doi: 10.1136/vr.j1405
No abstract available
Effect of the α2 -receptor agonists medetomidine, detomidine, xylazine, and romifidine on the ketamine metabolism in equines assessed with enantioselective capillary electrophoresis.
Electrophoresis    March 20, 2017   Volume 38, Issue 15 1895-1904 doi: 10.1002/elps.201700017
Sandbaumhüter FA, Theurillat R, Bettschart-Wolfensberger R, Thormann W.The combination of ketamine and an α -receptor agonist is often used in veterinary medicine. Four different α -receptor agonists, medetomidine, detomidine, xylazine, and romifidine, which differ in their chemical structure and thus in selectivity for the α -receptor and in the sedative and analgesic potency, are typically employed during surgery of equines. Recovery following anesthesia with ketamine and an α -receptor agonist is dependent on the α -receptor agonist. This prompted us to investigate (i) the inhibition characteristics for the N-demethylation of ketamine to norketamine and (...
Chromobacterium violaceum Infection in a Horse.
Journal of comparative pathology    March 17, 2017   Volume 156, Issue 4 334-338 doi: 10.1016/j.jcpa.2017.02.004
Hammerschmitt ME, Rolim VM, Snel GGM, Siqueira FM, Driemeier D, Pavarini SP.Chromobacterium violaceum is an opportunistic pathogen of mammals that produces characteristic violet pigment in bacterial culture. We report pneumonia and septicaemia caused by C. violaceum in a horse. Necropsy examination was performed on a 3-year-old Quarter Horse stallion with a history of recurrent episodes of pneumonia, fever, dyspnoea and sanguineous nasal discharge. The lungs were not collapsed, but they contained dark red foci mixed with white areas, and multiple nodules of firm consistency. Within the liver and kidney there were randomly distributed, multifocal, white pinpoint lesion...
In vitro phase I metabolism of selective estrogen receptor modulators in horse using ultra-high performance liquid chromatography-high resolution mass spectrometry.
Drug testing and analysis    February 16, 2017   Volume 9, Issue 9 1349-1362 doi: 10.1002/dta.2158
Kwok KY, Chan GHM, Kwok WH, Wong JKY, Wan TSM.Selective estrogen receptor modulators (SERMs) are chemicals that possess the anti-oestrogenic activities that are banned 'in' and 'out' of competition by the World Anti-Doping Agency (WADA) in human sports, and by the International Federation of Horseracing Authorities (IFHA) in horseracing. SERMs can be used as performance-enhancing drugs to boost the level of androgens or to compensate for the adverse effects as a result of extensive use of androgenic anabolic steroids (AASs). SERMs have indeed been abused in human sports; hence, a similar threat can be envisaged in horseracing. Numerous an...
Prevalence of Equine Hepacivirus Infections in France and Evidence for Two Viral Subtypes Circulating Worldwide.
Transboundary and emerging diseases    November 24, 2016   Volume 64, Issue 6 1884-1897 doi: 10.1111/tbed.12587
Pronost S, Hue E, Fortier C, Foursin M, Fortier G, Desbrosse F, Rey FA, Pitel PH, Richard E, Saunier B.Like hepatitis C virus (HCV) in humans, the newly identified equine hepacivirus (NPHV) displays a predominating liver tropism that may evolve into chronic infections. The genomes of the two viruses share several organizational and functional features and are phylogenetically closest amongst the Hepacivirus genus. A limited amount of data is available regarding the spread of hepacivirus infections in horses. In this study, we asked whether in a more representative sample the prevalence and distribution of NPHV infections in France would resemble that reported so far in other countries. A total ...
Transcriptome profiling of equine vitamin E deficient neuroaxonal dystrophy identifies upregulation of liver X receptor target genes.
Free radical biology & medicine    October 15, 2016   Volume 101 261-271 doi: 10.1016/j.freeradbiomed.2016.10.009
Finno CJ, Bordbari MH, Valberg SJ, Lee D, Herron J, Hines K, Monsour T, Scott E, Bannasch DL, Mickelson J, Xu L.Specific spontaneous heritable neurodegenerative diseases have been associated with lower serum and cerebrospinal fluid α-tocopherol (α-TOH) concentrations. Equine neuroaxonal dystrophy (eNAD) has similar histologic lesions to human ataxia with vitamin E deficiency caused by mutations in the α-TOH transfer protein gene (TTPA). Mutations in TTPA are not present with eNAD and the molecular basis remains unknown. Given the neuropathologic phenotypic similarity of the conditions, we assessed the molecular basis of eNAD by global transcriptome sequencing of the cervical spinal cord. Differential...
Autopsy imaging for cardiac tamponade in a Thoroughbred foal.
Journal of equine science    September 30, 2016   Volume 27, Issue 3 115-118 doi: 10.1294/jes.27.115
Yamada K, Sato F, Horiuchi N, Higuchi T, Kobayashi Y, Sasaki N, Nambo Y.Autopsy imaging (Ai), postmortem imaging before necropsy, is used in human forensic medicine. Ai was performed using computed tomography (CT) for a 1-month-old Thoroughbred foal cadaver found in a pasture. CT revealed pericardial effusion, collapse of the aorta, bleeding in the lung lobe, gas in the ventricles and liver parenchyma, and distension of the digestive tract. Rupture in the left auricle was confirmed by necropsy; however, it was not depicted on CT. Therefore, Ai and conventional necropsy are considered to complement each other. The cause of death was determined to be traumatic cardi...
Equine hepatocytes: isolation, cryopreservation, and applications to in vitro drug metabolism studies.
Pharmacology research & perspectives    September 30, 2016   Volume 4, Issue 5 e00268 doi: 10.1002/prp2.268
Shibany KA, Tötemeyer S, Pratt SL, Paine SW.Despite reports of the successful isolation of primary equine hepatocytes, there are no published data regarding the successful cryopreservation of these isolated cells. In this study, a detailed description of the procedures for isolation, cryopreservation, and recovery of equine hepatocytes are presented. Furthermore, the intrinsic clearance (Cl) and production of metabolites for three drugs were compared between freshly isolated and recovered cryopreserved hepatocytes. Primary equine hepatocytes were isolated using a two-step collagenase perfusion method, with an average cell yield of 2.47...
Acute and chronic infections with nonprimate hepacivirus in young horses.
Veterinary research    September 22, 2016   Volume 47, Issue 1 97 doi: 10.1186/s13567-016-0381-6
Gather T, Walter S, Pfaender S, Todt D, Feige K, Steinmann E, Cavalleri JM.The recently discovered nonprimate hepacivirus (NPHV) naturally infects horses and is the closest known homolog of hepatitis C virus to date. Within a follow-up study acute field infections were monitored in four young Thoroughbred horses until the ages of 12-13 months. Serum samples were analyzed for the presence of NPHV RNA and anti-NPHV NS3 antibodies and liver specific parameters were evaluated. The four young horses were not able to clear infection, but remained chronically infected for the entire monitored time period despite the presence of NPHV specific antibodies.
Presumptive Iatrogenic Microcystin-Associated Liver Failure and Encephalopathy in a Holsteiner Gelding.
Journal of veterinary internal medicine    September 9, 2016   Volume 30, Issue 5 1747-1751 doi: 10.1111/jvim.14571
Mittelman NS, Engiles JB, Murphy L, Vudathala D, Johnson AL.An 8-year-old Holsteiner gelding was presented for evaluation of anorexia, obtundation, icterus, and mild colic signs of 48 hours duration. History, physical examination, and initial diagnostics were suggestive of hepatic disease and encephalopathy. Microcystin toxicosis was suspected based on historical administration of a cyanobacteria supplement, associated serum biochemistry abnormalities, and characteristic histopathological changes. Microcystin contamination was confirmed in both supplement containers fed to the horse. Fulminant hepatic failure and encephalopathy progressed resulting in ...
Analysis of phenylbutazone residues in horse tissues with and without enzyme-hydrolysis by LC-MS/MS.
Drug testing and analysis    July 23, 2016   Volume 8, Issue 5-6 535-538 doi: 10.1002/dta.2020
Boison JO, Dowling T, Johnson R, Kinar J.Phenylbutazone (PBZ) is permitted to be used for the treatment of musculoskeletal pain and inflammation in race horses but it is not approved for use in horses destined for human consumption. In a recent study initiated in our laboratory to study the disposition of PBZ and its oxyphenbutazone (OXPBZ) metabolite in equine tissues, we compared the effect of an additional enzymatic hydrolysis step with ß-glucuronidase on the results of the analysis for PBZ without enzymatic hydrolysis. Incurred tissue samples obtained from a female horse dosed with PBZ at 8.8 mg/kg for 3 days and sacrificed ...
Ultrasonographically visible hepatic location in clinically normal horses.
Australian veterinary journal    May 31, 2016   Volume 94, Issue 6 192-196 doi: 10.1111/avj.12448
Johns IC, Miles A.Ultrasound is widely used for evaluating horses with suspected liver dysfunction. Although a change in size is considered suggestive of pathology, no clear guidelines exist to define the hepatic ultrasonographically visible locations (HUVL) in horses. The aim of the study was to describe the HUVL in normal horses and determine whether this is altered by signalment, height, weight and body condition score (BCS). Methods: Prospective observational study. Methods: Bilateral ultrasonographic evaluation was performed in 58 clinically normal horses with no history of hepatic disease. The most crania...
Prevalence of liver fluke infection in Irish horses and assessment of a serological test for diagnosis of equine fasciolosis.
Equine veterinary journal    May 27, 2016   Volume 49, Issue 2 183-188 doi: 10.1111/evj.12577
Quigley A, Sekiya M, Egan S, Wolfe A, Negredo C, Mulcahy G.There is little information on the prevalence of Fasciola hepatica infection in the horse population in Ireland or the potential impact of fluke infection on animal health. Objective: To investigate F. hepatica infection in the Irish horse population and to assess the diagnostic potential of an indirect enzyme-linked immunosorbent assay (ELISA) based on the F. hepatica recombinant cathepsin L1 (CL1) antigen. Methods: Cross-sectional abattoir survey of horses for liver fluke status. Methods: Animals (n = 200) were examined at an abattoir between May 2013 and April 2014. Horses were graded ante ...
Equine Mesenchymal Stromal Cells from Different Sources Efficiently Differentiate into Hepatocyte-Like Cells.
Tissue engineering. Part C, Methods    May 18, 2016   Volume 22, Issue 6 596-607 doi: 10.1089/ten.TEC.2015.0403
Pennington MR, Curtis TM, Divers TJ, Wagner B, Ness SL, Tennant BC, Van de Walle GR.Adult equine hepatocytes have proven challenging to culture long term in vitro as they rapidly lose their morphology and functionality, thus limiting studies on liver function and response to disease. In this study, we describe for the first time the differentiation of equine mesenchymal stromal cells (MSC) from a variety of sources into functional hepatocyte-like cells (HLC). First, we differentiated equine umbilical cord blood (UCB)-derived MSC into HLC and found that these cells exhibited a distinct polygonal morphology, stored glycogen as visualized by periodic acid Schiff's reagent staini...
Characterization of equine cytochrome P450: role of CYP3A in the metabolism of diazepam.
Journal of veterinary pharmacology and therapeutics    March 11, 2016   Volume 39, Issue 5 478-487 doi: 10.1111/jvp.12303
Nakayama SM, Ikenaka Y, Hayami A, Mizukawa H, Darwish WS, Watanabe KP, Kawai YK, Ishizuka M.Research on drug metabolism and pharmacokinetics in large animal species including the horse is scarce because of the challenges in conducting in vivo studies. The metabolic reactions catalyzed by cytochrome P450s (CYPs) are central to drug pharmacokinetics. This study elucidated the characteristics of equine CYPs using diazepam (DZP) as a model compound as this drug is widely used as an anesthetic and sedative in horses, and is principally metabolized by CYPs. Diazepam metabolic activities were measured in vitro using horse and rat liver microsomes to clarify the species differences in enzy...
Congenital diaphragmatic hernia with concurrent aplasia of the pericardium in a foal.
BMC veterinary research    December 30, 2015   Volume 11 309 doi: 10.1186/s12917-015-0623-2
Tăbăran AF, Nagy AL, Cătoi C, Morar I, Tăbăran A, Mihaiu M, Bolfa P.In veterinary medicine congenital abnormalities of the diaphragm and pericardium are rare, idiopathic malformations, being reported mainly in dogs. This report documents an unusual case of developmental defects in a foal consisting of diaphragmatic hernia concurrent with pericardial aplasia. Methods: Following a normal delivery, a full term, female Friesian stillborn foal with the placenta was presented for necropsy. External morphological examination indicated a normally developed foal. At necropsy, a large oval defect (approximately 20 × 15 cm in size) was observed in the left-dorsal si...
Effects of deoxynivalenol in naturally contaminated wheat on feed intake and health status of horses.
Mycotoxin research    September 30, 2015   Volume 31, Issue 4 209-216 doi: 10.1007/s12550-015-0234-6
Schulz AK, Kersten S, Dänicke S, Coenen M, Vervuert I.The present study examined the short-term effects of deoxynivalenol (DON), administered at two different concentrations via a feed preparation using naturally contaminated wheat, on feed intake, liver and kidney metabolism and immunomodulatory properties in horses. Twelve geldings were randomly assigned to one of three dietary treatments for 21 days. DON was provided via naturally contaminated wheat (14.6 ± 6.5 mg DON/kg dry matter). The daily feed intake was adjusted to 4 kg of wheat and 1.7 kg of silage per 100 kg of body weight (BW). Horses were fed one of the following diets: control whea...
Clinical Research Abstracts of the British Equine Veterinary Association Congress 2015.
Equine veterinary journal    September 17, 2015   Volume 47 Suppl 48 28 doi: 10.1111/evj.12486_63
Lotstra RJ, van den Broek J, Power T, Marr CM, Wijnberg ID.Atrial fibrillation is a common equine arrhythmia. Quinidine alone, or with digoxin are common treatments. Studies on outcome in Warmblood populations in which duration of the AF is often unknown are limited. Objective: To identify the factors that are associated with the success of full treatment cardioversion with oral medication, and establish whether there are differences in these factors between institutions. Methods: Retrospective case series using patient records of Equine University Clinic of Utrecht University and Rossdales Equine Hospital, Newmarket. Methods: Forty-nine horses treate...
Metabolic studies of oxyguno in horses.
Analytica chimica acta    August 24, 2015   Volume 891 190-202 doi: 10.1016/j.aca.2015.08.006
Wong AS, Ho EN, Wan TS, Lam KK, Stewart BD.Oxyguno (4-chloro-17α-methyl-17β-hydroxy-androst-4-ene-3,11-dione) is a synthetic oral anabolic androgenic steroid commercially available without a prescription. Manufacturers of oxyguno claim that its anabolic effect in metabolic enhancement exceeds that of the classic anabolic steroid testosterone by seven times, but its androgenic side-effects are only twelve percent of testosterone. Like other anabolic androgenic steroids, oxyguno is prohibited in equine sports. The metabolism of oxyguno in either human or horse has not been reported and therefore little is known about its metabolic fate...
Equine insulin receptor and insulin-like growth factor-1 receptor expression in digital lamellar tissue and insulin target tissues.
Equine veterinary journal    August 21, 2015   Volume 48, Issue 5 626-632 doi: 10.1111/evj.12474
Kullmann A, Weber PS, Bishop JB, Roux TM, Norby B, Burns TA, McCutcheon LJ, Belknap JK, Geor RJ.Hyperinsulinaemia is implicated in the pathogenesis of endocrinopathic laminitis. Insulin can bind to different receptors: two insulin receptor isoforms (InsR-A and InsR-B), insulin-like growth factor-1 receptor (IGF-1R) and InsR/IGF-1R hybrid receptor (Hybrid). Currently, mRNA expression of these receptors in equine tissues and the influence of body type and dietary carbohydrate intake on expression of these receptors is not known. Objective: The study objectives were to characterise InsR-A, InsR-B, IGF-1R and Hybrid expression in lamellar tissue (LT) and insulin responsive tissues from horse...
Musculoskeletal Health, Kidney and Liver Function in Retired Jockeys.
International journal of sports medicine    July 24, 2015   Volume 36, Issue 12 968-973 doi: 10.1055/s-0035-1548889
Cullen S, Donohoe A, McGoldrick A, McCaffrey N, Davenport C, Byrne B, Donaghy C, Tormey W, Smith D, Warrington G.The long-term implications of making-weight daily on musculoskeletal health and functioning of the kidney and liver remain unknown. This study aimed to investigate musculoskeletal health and kidney and liver function in a group of retired jockeys. 28 retired male jockeys (age 50-70 years) provided fasting blood samples for markers of bone metabolism and kidney and liver function. A dual-energy x-ray absorptiometry (DXA) scan was performed for the assessment of bone mineral density (BMD). Established reference ranges were used for interpretation of results. Comparisons were made between retired...
Metabolic study of androsta-1,4,6-triene-3,17-dione in horses using liquid chromatography/high resolution mass spectrometry.
The Journal of steroid biochemistry and molecular biology    May 29, 2015   Volume 152 142-154 doi: 10.1016/j.jsbmb.2015.05.011
Kwok WH, Leung GN, Wan TS, Curl P, Schiff PJ.Androsta-1,4,6-triene-3,17-dione (ATD) is an irreversible steroidal aromatase inhibitor and is marketed as a supplement. It has been reported to effectively reduce estrogen biosynthesis and significantly increase the levels of endogenous steroids such as dihydrotestosterone and testosterone in human. ATD abuses have been reported in human sports. Its metabolism in human has been studied, and the in vitro metabolic study of ATD in horses has been reported, however, little is known about its biotransformation and elimination in horses. This paper describes the in vitro and in vivo metabolism stu...
Carotenoids and fat-soluble vitamins in horse tissues: a comparison with cattle.
Animal : an international journal of animal bioscience    March 17, 2015   Volume 9, Issue 7 1230-1238 doi: 10.1017/S1751731115000415
Álvarez R, Meléndez-Martínez AJ, Vicario IM, Alcalde MJ.Carotenoids are important for human health because of their provitamin A function among other biological actions. Their implication on consumer point of view of cattle products have been widely studied, but very little information is available for horse products. The aim of this study was to study the accumulation of carotenoids, retinoids and tocopherol by HPLC and HPLC-MS analysis in different horse tissues (plasma, milk, adipose tissue and liver) and compare it with that of cattle. Fat color was also studied. Four groups of animals were studied (15 animals within each group): lactating mare...
Experimental transmission of equine hepacivirus in horses as a model for hepatitis C virus.
Hepatology (Baltimore, Md.)    February 24, 2015   Volume 61, Issue 5 1533-1546 doi: 10.1002/hep.27689
Ramsay JD, Evanoff R, Wilkinson TE, Divers TJ, Knowles DP, Mealey RH.Equine hepacivirus (EHCV; nonprimate hepacivirus) is a hepatotropic member of the Flaviviridae family that infects horses. Although EHCV is the closest known relative to hepatitis C virus (HCV), its complete replication kinetics in vivo have not been described, and direct evidence that it causes hepatitis has been lacking. In this study, we detected EHCV in 2 horses that developed post-transfusion hepatitis. Plasma and serum from these horses were used to experimentally transmit EHCV to 4 young adult Arabian horses, two 1-month-old foals (1 Arabian and 1 Arabian-pony cross), and 2 foals (1 Ara...
Inhibition of in vitro metabolism of testosterone in human, dog and horse liver microsomes to investigate species differences.
Toxicology in vitro : an international journal published in association with BIBRA    January 3, 2015   Volume 29, Issue 3 468-478 doi: 10.1016/j.tiv.2014.12.018
Zielinski J, Mevissen M.Testosterone hydroxylation was investigated in human, canine and equine liver microsomes and in human and canine single CYPs. The contribution of the CYP families 1, 2 and 3 was studied using chemical inhibitors. Testosterone metabolites were analyzed by HPLC. The metabolites androstenedione, 6β- and 11β-hydroxytestosterone were found in microsomes of all species, but the pattern of metabolites varied within species. Androstenedione was more prominent in the animal species, and an increase over time was seen in equines. Testosterone hydroxylation was predominantly catalyzed by the CYP3A subf...
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