The use of single sample clearance estimates to probe hepatic drug metabolism in rats. II

Bachmann, Kenneth; Jahn, D.; Yang, Chenguang; Schwartz, J

doi:10.3109/00498258809041652

Cited by 9 publications

(6 citation statements)

References 12 publications

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“…Bachmann et al estimated the clearance of racethosuximide to be around 0.022 l/h/kg after a 35 mg/kg dose and 0.027 l/h/kg after a 5 mg/kg dose using an achiral analytical procedure (EMIT) [8,9]; these values are considerably lower than those observed in this present study. Bachmann et al [9] also found the apparent volume of distribution to be 0.70+0.031 l/kg; these values were close to the lower end of the range observed in this current work.…”

Section: Pharmacokinetic Parameterscontrasting

confidence: 56%

The pharmacokinetics of ethosuximide enantiomers in the rat

Mifsud

Collier

Millership

2001

Biopharm & Drug Disp

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A chiral gas chromatographic assay previously developed for quantitative analysis of ethosuximide and its major metabolites in rat urine has been adapted for the analysis of the drug in plasma. Ethosuximide, both as a racemic mixture and as the individual enantiomers, was administered to conscious rats by the intravenous (i.v.) and intraperitoneal (i.p.) routes. Pharmacokinetic parameters were estimated using standard non-compartmental methods. Comparison of the pharmacokinetic parameters of (S)-ethosuximide and (R)-ethosuximide showed that total body clearance of (R)-ethosuximide was significantly larger than that of (S)-ethosuximide and that elimination half-life was significantly shorter following administration of both 40 mg i.v. and i.p. doses, indicating that there is stereoselective elimination of ethosuximide. However, no significant differences were found between apparent volumes of distribution. In addition, no significant differences were found for either enantiomer between the estimates of the pharmacokinetic parameters obtained following administration as the individual enantiomer and as a constituent of the racemic mixture. This indicates that, at the doses studied, the preferential faster elimination of (R)-ethosuximide is not dependent upon the presence of the (S)-enantiomer. Also, for each enantiomer, the lack of any significant difference between estimates of clearance when administered as part of a racemic mixture and when administered separately indicates that neither enantiomer affects the clearance of the other.

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Section: Pharmacokinetic Parameterscontrasting

confidence: 56%

The pharmacokinetics of ethosuximide enantiomers in the rat

Mifsud

Collier

Millership

2001

Biopharm & Drug Disp

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“…where D represents the dose of probe drug in mg/kg; V is volume of distribution (1/kg); t is the sampling time (h); and Ct is the plasma concentration of the drug (mg/1) at time t. This method of determining single sample clearance estimates (CL) has been described previously [15].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Blood samples were drawn at previously determined sampling times which permitted probe clearances to be estimated from single measurements of probe concentrations in plasma as previously described [15]. Post-dose sampling times were as follows: theophylline.…”

Section: Blood Samplingmentioning

confidence: 99%

The Influence of Anesthetic Agents on Rat Hepatic Cytochromes P450 in vivo

Loch

Potter

Bachmann³

1995

Pharmacology

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The objective of this study was to identify which anesthetics when used acutely will affect cytochrome P450 (CYP) activity in male Sprague-Dawley rats in vivo. The anesthetics tested were fentanyl citrate, α-chloralose, ketamine, urethane (ethyl carbamate), halothane, and ether. CO₂ anesthesia was used as the control comparator. Theophylline was used as a probe for CYP1A activity, phenobarbital for CYP2B/2C, flecainide for CYP2D1, and ethosuximide for CYP 3A activity. All probes were administered via tail vein injection after anesthetic-induced loss of the righting reflex. Single sample probe clearances were estimated, and used as an index of CYP activity. Fentanyl citrate, α-chloralose, halothane, and ether did not have statistically significant effects on any of the CYP activities. Ketamine did not significantly affect CYP1 or CYP2B/ 2C activity. However, it decreased the clearance of flecainide (i.e. CYP2D1 activity) by 13.4% (p < 0.001) and the clearance of ethosuximide (i.e. CYP3A activity) by 17.6% (p < 0.0001). Urethane increased the clearance of theophylline by 91.5% (p < 0.0001), and decreased the clearance of ethosuximide by 40.5% (p < 0.0001) though it did not affect CYP2B/2C or CYP2D1 activities significantly. From this data, we conclude that a single dose of ketamine mildly inhibits the activity of CYP2D1 and CYP3A, and a single dose of urethane strongly inhibits CYP3A but increases CYP1A activity.

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“…Theophylline CL was estimated from plasma con centration measurements in samples acquired from blood drawn 6 h after theophylline administration ac cording to the following equation [5]:…”

Section: Theophylline Administration and Measurementmentioning

confidence: 99%

In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

Bachmann

Sanyal²,

Potter³

et al. 1993

Pharmacology

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The role of various subfamilies of rat hepatic cytochrome P-450 in the oxidation of theophylline was evaluated by comparing theophylline clearance in control rats and those pretreated with relatively selective inducers and inhibitors of the cyto-chromes P-450. Pretreatment with the CYP1A inducer, β-naphthofiavone (BNF), increased theophylline clearance 4.5-fold (p < 0.001), and the CYP1A inhibitor, α-naphthoflavone, significantly attenuated the BNF effect. Pretreatment with phenobarbital, an inducer of CYP2B/C in rats, had a far more modest effect, increasing theophylline clearance only 1.6-fold (p < 0.005). The phenobarbital-mediated increase in theophylline clearance was attenuated by orphenadrine, a CYP2B/C inhibitor. The CYP2E inducer, isoniazid and the CYP2E inhibitor, diallyl sulfïde were virtually without effect, as was the CYP4A inducer, clofibrate, and the CYP4A inhibitor, 10-undecynoic acid. Ajmaline, and inhibitor of CYP2D, was also without any effect on theophylline clearance. While the powerful CYP3A inducer clotrimazole did not increase theophylline clearance, troleandomycin, an inhibitor of CYP3A, did slow theophylline clearance by about 25% (p < 0.002). Together, these findings suggest that CYP1A is principally responsible for the overall oxidation of theophylline in rats, and that CYP2B/C probably also mediates some theophylline oxidation. The involvement of CYP2D, CYP2E, CYP4A, and CYP3A is relatively trivial.

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The use of single sample clearance estimates to probe hepatic drug metabolism in rats. II

Cited by 9 publications

References 12 publications

The pharmacokinetics of ethosuximide enantiomers in the rat

The pharmacokinetics of ethosuximide enantiomers in the rat

The Influence of Anesthetic Agents on Rat Hepatic Cytochromes P450 in vivo

In vivo Evidence that Theophylline Is Metabolized Principally by CYP1A in Rats

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