Pharmacodynamic effects and pharmacokinetic profiles of keto-doxapram and doxapram in newborn lambs.
Keto-doxapram (keto-dox), an oxidative metabolite of doxapram, is a possible ventilatory stimulating agent. Our study characterizes its ventilatory properties, pharmacodynamic effects, and pharmacokinetic profile, and those of its parent compound, doxapram. Two groups of five awake, unsedated, newborn lambs (2- to 6-d old) received, respectively, i.v. infusions of keto-dox or doxapram (2.5 mg/kg) over a period of 1 min. Ventilatory parameters were continuously recorded before and for 1 h after the drug infusion. The pharmacokinetic profiles of both drugs were determined from blood samples collected serially before and after drug injection. Both drugs stimulated ventilation. Keto-dox increased baseline minute ventilation by 46 +/- 6.1% and 27.8 +/- 8.1% (p less than 0.002) at 1 and 5 min, respectively, an effect that decreased after 5 min of infusion. Doxapram increased minute ventilation by 57 +/- 9% (p less than 0.002) at 1 min, and by 48 +/- 7% at 5 min, but its effect lasted for 20 min after injection. Compared with the effects of keto-dox, this doxapram increase was significantly higher (p less than 0.02). Also, doxapram, but not keto-dox, caused an increase in systolic blood pressure (from 110 +/- 3.5 to 118 +/- 3.4 mm Hg at 10 min, p less than 0.01), as well as a change in neuro-behavior. Both drugs exhibited a biexponential decay curve, characterized by a short alpha and a longer beta t1/2, but keto-dox has a faster elimination rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Jeremy Rill Apnea Research Network, Québec City, Montreal, Canada.
A
A
Bairam
P W
PW
Blanchard
K
K
Mullahoo
K
K
Beharry
N
N
Laudignon
J V
JV
Aranda
D000818:Animals; D000831:Animals, Newborn; D004315:Doxapram / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008657:Metabolic Clearance Rate; D012119:Respiration / Q000187:drug effects*; D012756:Sheep; D013268:Stimulation, Chemical
C029505:2-ketodoxapram; D004315:Doxapram