Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Single-dose studies by the intravenous, intramuscular, and oral routes

Boxenbaum, Harold; Geitner, K. A.; Jack, M.L.; Dixon, W. J.; Spiegel, Herbert E.; Symington, Julia; Christian, Robin A.; Moore, James D.; Weissman, Lester; Kaplan, Stanley A.

doi:10.1007/bf01064806

Cited by 43 publications

(7 citation statements)

References 35 publications

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“…As reported previously [38,39], absolute systemic avail ability was not significantly less than 100%, and not significantly altered by age or gen der. Thus, age appears not to influence the extent of chlordiazepoxide absorption from the gastrointestinal tract.…”

Section: Discussionsupporting

confidence: 56%

Age and Gender Effects on Chlordiazepoxide Kinetics: Relation to Antipyrine Disposition

et al. 1989

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Twelve normal subjects aged 24–41 years, and 12 subjects aged 62–79 years, received single 50-mg doses of chlordiazepoxide hydrochloride by mouth and by intravenous injection on two occasions. Chlordiazepoxide volume of distribution was significantly correlated with body weight (r = 0.63, p < 0.001), but was not related to age or sex. Among male subjects, elimination half-life was prolonged (20 vs. 8 h, p < 0.025) and clearance reduced (20 vs. 43 ml/min, p < 0.05) in elderly as opposed to young volunteers. Among women, there was no significant difference between elderly and young subjects in elimination half-life (12 vs. 13 h) or clearance (29 vs. 22 ml/min). Absolute bioavailability of oral chlordiazepoxide was not less than 100%, and was unrelated to age or sex. Among 20 subjects who received a single 1.0- to 1.2-gram intravenous dose of antipyrine on another occasion, clearance of chlordiazepoxide and of antipyrine were significantly correlated (r = 0.62, p < 0.01). Like many other low-clearance oxidatively metabolized compounds, chlordiazepoxide clearance is reduced and half-life prolonged in elderly men, but not elderly women. Individual variations in chlordiazepoxide clearance are significantly correlated with those of antipyrine, a drug commonly used as an index of hepatic oxidizing capacity.

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Section: Discussionsupporting

confidence: 56%

Age and Gender Effects on Chlordiazepoxide Kinetics: Relation to Antipyrine Disposition

et al. 1989

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“…A dose of 1 ml of this solution (50 mg of CDX· HCI or 44.6 mg of CDX) was mixed with 49 ml of 5% dextrose in water and infused, together with 250 to 500 ml of 5% dextrose in water, into an antecubital vein by a constant-rate infusion pump over a period of one hour. Venous blood samples were drawn through an indwelling butterfly cannula placed in the contralateral forearm, or by separate venipuncture, prior to drug administration, at the termination of the infusion and at 1.5, 2.0, 2.5, 3,4,6,8,12,24,36,48,60, and 72 hr after the start of the infusion. Heparinized whole blood samples were immediately frozen and kept so until the time of assay.…”

Section: Methodsmentioning

confidence: 99%

Kinetics of intravenous chlordiazepoxide: Sex differences in drug distribution

Dj¹,

Shader²,

Franke³

et al. 1977

Clin Pharma and Therapeutics

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Fourteen healthy subjects (7 male and 7 female) received 50 mg of chlordiazepoxide (CDX) hydrochloride by I‐hr intravenous infusion. Multiple venous blood samples drawn during the 72 hr after the infusion were assayed for whole blood concentrations of CDX and of its major metabolite, desmethylchlordiazepoxide (DMCDX). Mean (±SE) pharmacokinetic parameters, determined by weighted nonlinear least‐squares regression analysis, were: distribution half‐life, 1.3 (±0.3) hr; elimination half‐life, 17.8 (±2 .2) hr; volume of central compartment (VI), 0.27 (±0.02) Llkg; total distribution space (V.J, 0.52 (±0.03) Llkg; total clearance, 26.4 (±3.2) mllmin. Viand Vd were significantly larger among females (0.30 and 0.58 Llkg) than among males (0.22 and 0.45 Llkg), suggesting more extensive drug distribution in females. Values of half‐life and of clearance did not, however, differ significantly between sexes. A second study in three subjects compared simultaneous whole blood and plasma CDX concentrations after intravenous bolus injection and showed them to be highly correlated. Red cell :plasma partition ratios were 0, O.OJ, and 0.24, indicating limited uptake of CD X by red cells. Volumes of distribution and clearances calculated from CDX concentrations in whole blood are larger than those based on plasma concentrations.

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“…Unlike diazepam, TSPO occupancy by midazolam and chlordiazepoxide, the two other benzodiazepines with measurable affinity, would be expected to be negligible if clinical pharmacokinetic data are used to calculate likely competition at the TSPO at clinically relevant doses. A single dose of 30 mg chlordiazepoxide ( K i ∼ 5700 nM in HABs) orally produces a maximum concentration of 2 mg/L (equivalent to 6.67 μM; Boxebaum et al, ). Repeated dosing has been shown to produce a lower steady‐state of around 1.5 mg/L (Boxebaum et al, ).…”

Section: Demographic Details Of Brain Samplesmentioning

confidence: 99%

“…Repeated dosing has been shown to produce a lower steady‐state of around 1.5 mg/L (Boxebaum et al, ). However, 93% of chlordiazepoxide was found to be protein bound, suggesting that the free fraction is around 7% (equivalent to 473 nM; Boxenbaum et al, ). When this value was interpolated in the curve generated using our in vitro data, there was no block of specific binding expected to be observed.…”

Section: Demographic Details Of Brain Samplesmentioning

confidence: 99%

Are prescribed benzodiazepines likely to affect the availability of the 18 kDa translocator protein (TSPO) in PET studies?

Kalk

Owen

Tyacke

et al. 2013

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Pharmacokinetic and biopharmaceutic profile of chlordiazepoxide HCl in healthy subjects: Single-dose studies by the intravenous, intramuscular, and oral routes

Cited by 43 publications

References 35 publications

Age and Gender Effects on Chlordiazepoxide Kinetics: Relation to Antipyrine Disposition

Age and Gender Effects on Chlordiazepoxide Kinetics: Relation to Antipyrine Disposition

Kinetics of intravenous chlordiazepoxide: Sex differences in drug distribution

Are prescribed benzodiazepines likely to affect the availability of the 18 kDa translocator protein (TSPO) in PET studies?

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