Cytochrome P450‐dependent metabolism of midazolam in hepatic microsomes from chickens, turkeys, pheasant and bobwhite quail

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In vivo plasma pharmacokinetics of midazolam hydrochloride (5 mg/kg i.v.) were determined in commercially raised broiler chickens, turkeys, ring-necked pheasants and bobwhite quail. Pharmacokinetic profiles of midazolam were similar for all four species, especially with regard to the area under the plasma drug concentration-time curve. Estimates of the half-life of elimination of midazolam were 0.42, 1.45, 1.90, and 9.71 h for turkeys, chickens, bobwhite quail, and pheasant, respectively. This was similar to the major metabolite (1-hydroxymidazolam). Elimination half-lives for 1-hydroxymidazolam were 1.35, 1.86, 1.97, and 13.97 h for turkey, chicken, bobwhite quail and pheasant, respectively. Elimination half-lives for 4-hydroxymidazolam were 0.76, 1.23, 2.85, and 13.82 h for chicken, turkey, pheasant, and bobwhite quail, respectively. In addition to traditional pharmacokinetic approaches to parameter estimation, a bootstrapping technique was employed to attempt to achieve more realistic approximations of the concentrations at later time-points.

Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 96%

Plasma pharmacokinetics of midazolam in chickens, turkeys, pheasants and bobwhite quail

Cortright

Wetzlich

Craigmill

2007

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“…An attempt was made to use the Michaelis–Menton parameters for hepatic metabolism estimated from an earlier in vitro study (Cortright & Craigmill, 2006). However, the current study did not show zero order kinetics and to fit the experimental data the model V max value had to be increased so much as to approximate linear clearance.…”

Section: Discussionmentioning

confidence: 99%

“…This may be especially useful for predicting residues in so-called 'minor' species (fish, goats, sheep, pheasant and quail) where therapeutic drugs have been tested and approved for use in 'major' economic species, but not for minor species that are susceptible to the same diseases. Previous work by our laboratory has focused on comparative in vitro and in vivo drug studies to see if minor species pharmacokinetics ⁄ tissue residues can be modelled using empirical data from major species (Cortright & Craigmill, 2006;Cortright et al, 2007).The aim of the current paper is to describe the development and optimization of a PBPK model in chickens for the pharmacokinetics and tissue residues of midazolam after intravenous (i.v.) administration.…”

Section: Introductionmentioning

confidence: 99%

A PBPK model for midazolam in four avian species

Cortright

Wetzlich

Craigmill

2009

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A physiologically based pharmacokinetic (PBPK) model was developed for midazolam in the chicken and extended to three other species. Physiological parameters included organ weights obtained from 10 birds of each species and blood flows obtained from the literature. Partition coefficients for midazolam in tissues vs. plasma were estimated from drug residue data obtained at slaughter. The avian models include separate compartments for venous plasma, liver, kidney, muscle, fat and all other tissues. An estimate of total body clearance from an earlier in vitro study was used as a starting value in the model, assuming almost complete removal of the parent compound by liver metabolism. The model was optimized for the chicken with plasma and tissue data from a pharmacokinetic study after intravenous midazolam (5 mg/kg) dose. To determine which parameters had the most influence on the goodness of fit, a sensitivity analysis was performed. The optimized chicken model was then modified for the turkey, pheasant and quail. The models were validated with midazolam plasma and tissue residue data in the turkey, pheasant and quail. The PBPK models in the turkey, pheasant and quail provided good predictions of the observed tissue residues in each species, in particular for liver and kidney.

“…In addition, MDZ has already been used in different avian species as a substrate for CYP3A (Cortright & Craigmill, ). In chickens, the production of MDZ metabolites in liver microsomes demonstrated Michaelis–Menten kinetics with K m equal to 2.1 ± 0.8 μ m for 1‐OH‐MDZ (Cortright & Craigmill, ). Therefore, MDZ was also used in our study to evaluate the CYP3A activity in liver and intestines of the broilers.…”

Section: Discussionmentioning

confidence: 99%

Hepatic and intestinal CYP3A expression and activity in broilers

Osselaere

Bock

Eeckhaut

et al. 2013

Cytochrome P450 is involved in drug metabolism. Subfamily CYP3A shows a degree of similarity across different animal species. However, little information is available about its expression and activity in broiler chickens. A RT-PCR method was developed for the quantification of CYP3A37 expression in the liver and small intestine of broilers. A higher expression in the jejunum was observed compared with that in the ileum. In the liver, a significantly lower expression compared with that in the jejunum was noticed. Thus, the role of the small bowel in drug metabolism cannot be neglected in broilers. CYP3A activity was studied in vitro using midazolam as a substrate. Two protocols for the preparation of intestinal microsomes were compared. Mincing of the tissues before ultracentrifugation seemed to be more appropriate than a protocol based on ethylenediaminetetra-acetic acid separation. CYP3A activity revealed to be the highest in the duodenum with a decreasing trend towards the ileum. Activity in liver was comparable to duodenal activity.