In vitro evaluation of differences in phase 1 metabolism of ketamine and other analgesics among humans, horses, and dogs

OBJECTIVE: To investigate cytochrome P450 (CYP) enzymes involved in metabolism of racemic and S-ketamine in various species and to evaluate metabolic interactions of other analgesics with ketamine. SAMPLE POPULATION: Human, equine, and canine liver microsomes. PROCEDURES: An analgesic was concurrently incubated with luminogenic substrates specific for CYP 3A4 or CYP 2C9 and liver microsomes. The luminescence signal was detected and compared with the signal for negative control samples. Ketamine and norketamine enantiomers were determined by use of capillary electrophoresis. RESULTS: A concentration-dependent decrease in luminescence signal was detected for ibuprofen and diclofenac in the assay for CYP 2C9 in human and equine liver microsomes but not in the assay for CYP 3A4 and methadone or xylazine in any of the species. Coincubation of methadone or xylazine with ketamine resulted in a decrease in norketamine formation in equine and canine liver microsomes but not in human liver microsomes. In all species, norketamine formation was not affected by ibuprofen, but diclofenac reduced norketamine formation in human liver microsomes. A higher rate of metabolism was detected for S-ketamine in equine liver microsomes, compared with the rate for the S-enantiomer in the racemic mixture when incubated with any of the analgesics investigated. CONCLUSIONS AND CLINICAL RELEVANCE: Enzymes of the CYP 3A4 family and orthologs of CYP 2C9 were involved in ketamine metabolism in horses, dogs, and humans. Methadone and xylazine inhibited in vitro metabolism of ketamine. Therefore, higher concentrations and diminished clearance of ketamine may cause adverse effects when administered concurrently with other analgesics.

In vitro metabolism of testosterone in the horse liver and involvement of equine CYPs 3A89, 3A94 and 3A95

Testosterone (TES) 6-β-hydroxylation is a significant metabolic step in the biotransformation of TES in human liver microsomes and reflects cytochrome P450 (CYP) 3A4/5 specific metabolic activity. Several CYP3A enzymes have been annotated in the horse genome, but functional characterization is missing. This descriptive study investigates TES metabolism in the horse liver in vitro and the qualitative contribution of three CYP3A isoforms of the horse. Metabolism of TES was investigated by using equine hepatocyte primary cultures and liver microsomes. Chemical inhibitors were used to determine the CYPs involved in TES biotransformation in equine microsomes. Single CYPs 3A89, 3A94, and 3A95, recombinantly expressed in V79 hamster lung fibroblasts, were incubated with TES and the fluorescent metabolite 7-benzyloxy-4-trifluoromethylcoumarin (BFC). The effect of ketoconazole and troleandomycin was evaluated on single CYPs. Testosterone metabolites were analyzed by HPLC and confirmed by GC/MS. In hepatocyte primary cultures, the most abundant metabolite was androstenedione (AS), whereas in liver microsomes, 6-β-hydroxytestosterone showed the largest peak. Formation of 6-β-hydroxytestosterone and 11-β-hydroxytestosterone in liver microsomes was inhibited by ketoconazole, troleandomycin, and quercetin. Equine recombinant CYP3A95 catalyzed 11-β-hydroxylation of testosterone (TES). Metabolism of BFC was significantly inhibited by ketoconazole in CYP3A95, whereas troleandomycin affected the activities of CYP3A94 and CYP3A95. Both inhibitors had no significant effect on CYP3A89. Metabolic reactions and effects of inhibitors differed between the equine CYP3A isoforms investigated. This has to be considered in future in vitro studies.

Idea de el Buen Pastor copiada por los SS. Doctores : representada en empresas sacras con avisos Espirituales, Morales, Politicos y Economicos para el govierno de un Principe Eclesiastico : divididas en dos partes, dedicadas en esta segunda parte ... $c / compuesta por ... Francisco Nuñez de Cepeda de la Compañia de Iesus

Sign.:[ ]2, 2E-2T8, 2V6, 2X-2Z4, 3A-3O4, 2X-2Z4, 3A4, 3B2

Resumen historico de la vida, virtudes y milagros del beato Lorenzo de Brindis General del orden de Capuchinos : sacado en italiano de los procesos presentados a la Sagrada Congregacion de ritos : dividido en tres partes

Índice

Ecclesiasticae historiae breviarium

Índices.

Historia General de España

Sign. : []2, [calderón]-6[calderón]2, 7[calderón], a-q4, A-Z4, 2A-2Z4, 3A4, 3B2

Historia de la vida del hombre [Texto impreso]

Tit. en antep.: "Historia de la vida del hombre"

Buen uso de la theologia moral: segun la doctrina, y espiritu de la Iglesia [Texto impreso]

T. II impreso en 1792

El medico y cirujano de los pobres ... : obras medico-chyrurgicas ... y otros tratados curiosos que en la quinta impression diò à luz en idioma francès Mr. Dubé /

Mode of access: Internet.

Introductio ad libros historicos Bibliorum Veteris Testamenti, praecognita critica et historica, ac autoritatis vindicias exponens /

Mode of access: Internet.

Authentica S. S. quatuor evangelistarum fides adversus omnes repugnantes haereticos ethnicosque philosophos ... /

Mode of access: Internet.

De Nederlandtse Herbarius of Kruydt-Boeck : beschryvende de Geslachten Gedaente Plaetse ... die in de Nederlanden in 't wilde gewonden ... /

Mode of access: Internet.

Raccolta di tutti gli antichi poeti latini co la loro versione nell'italiana favella : tomo decimonono : contiene le prime tre commedie /

Vita di Publio Terenzio scritta dal signor d. Filippo Argelati ; Andria ; Heautontimoroumenos, ovvero Il punitore di se stesso ; Eunuco.

Lucae Antonii Portii ... Opera omnia, medica, philosophica, et mathematica ih unum collecta : atque ad meliorem commadioremque formam redacta /

Mode of access: Internet.

L'anatomie d'Heister : avec des essais de physique sur l'usage des parties du corps humain [et] sur le méchanisme de leurs mouvemens, enrichie de nouvelles figures ... /

Mode of access: Internet.