A pharmacokinetic study of doxapram in patients and volunteers.

Abstract

1. Following intravenous bolus injections or brief infusions in healthy volunteers, plasma concentrations of doxapram declined in a multi‐ exponential fashion. The mean half‐life from 4‐12 h was 3.4 h (range 2.4‐4.1h), the mean apparent volume of distribution was 1.5 1 kg‐1 and the whole body clearance was 370 ml min‐1. 2. Enteric‐coated capsules of doxapram base were absorbed rapidly after an initial delay, and the systemic availability was about 60%. 3. Doxapram is extensively metabolized and less than 5% of an i.v. dose was excreted unchanged in the urine in 24 h. A metabolite (AHR 5955) was present in plasma in amounts comparable to the parent compound and had a similar half‐life. 4. The disposition of doxapram appears to be similar in healthy volunteers and patients with respiratory failure. 5. The previously held belief that plasma concentrations fall rapidly when an infusion is stopped is only true following short duration infusions. The pharmacokinetic properties of doxapram are such that steady‐state plasma concentrations will not be achieved for many hours with the recommended constant rate infusion regime.

The Ventilatory Effects of Doxapram in Normal Man

“…After 20 min the infusion rate was progressively decreased to maintain a constant plasma doxapram level, which ranged from 1.6 to 3.0 pg/ml. These levels are known to be similar to those attained in patients receiving doxapram infusions at the manufacturers' recommended rate [9]. The individual infusion rates were predicted from the previous pharmacokinetic data and were known to be without serious side effects [9].…”

“…The ECG was monitored throughout and taped music was provided through headphones to distract the subject from his environment. The side effects of doxapram and its long half-life [9] precluded a single blind cross-over study design.…”

“…These levels are known to be similar to those attained in patients receiving doxapram infusions at the manufacturers' recommended rate [9]. The individual infusion rates were predicted from the previous pharmacokinetic data and were known to be without serious side effects [9]. Blood was sampled at intervals from an indwelling venous cannula in the other forearm, for measurements of plasma doxapram concentration by gas-liquid chromatography [lo].…”

Hepatic necrosis with doxapram hydrochloride

“…Doxapram is oxidized to its principle metabolite (AHR 5955) by the liver and an enterohepatic pathway has been suggested with the bile an important excretory route (Robson & Prescott, 1978). It is unknown whether this metabolite has any pharmacological activity (Martindale, 28th Ed, 1982).…”

Pharmacokinetics of Doxapram in Idiopathic Apnea of Prematurity

“…In the last 10 years the use of aminophylline and caffeine respiratory depression associated with the administration of narcotics to mothers [7], recent publications [8][9][10][11][12][13] have reported its successful use to control neonatal apnea un responsive to standard therapy. Although pharmacokinetic studies have been con ducted in adults [14][15][16], information on the pharmacokinetics of doxapram in newborn infants was scarce [8,17]. This report de scribes the pharmacokinetics of doxapram as determined from plasma levels obtained during continuous intravenous infusion of doxapram hydrochloride in 13 premature in fants with apnea unresponsive to aminophylline or caffeine.…”