The antipyrine breath test in the rat: a pharmacokinetic model.
Breath tests have been widely advocated for use as non-invasive probes of mixed function oxidase activity in vivo. A catenary sequence of events begins with demethylation and results in the exhalation of 14CO2. Intermediates in this chain include formaldehyde and formate. In this current study [14C]-antipyrine, [14C]-formaldehyde and [14C]-formate have been administered to rats. The data from these one carbon intermediates lead to the conclusion that demethylation is not the rate-limiting step in the antipyrine breath test in the rat. The resultant 14CO2 exhalation rate time profiles have been used to derive a compartmental pharmacokinetic model for the antipyrine breath test in the rat. The simplest catenary model (Antipyrine----formaldehyde----formate----CO2) did not adequately describe the observed data. A compartment in equilibrium with the central compartment for formate was needed to characterize fully the observed data. The derived compartmental model was able to predict qualitatively the effects of phenobarbitone induction on the antipyrine breath test. The quantitative agreement between the model prediction and the observed data could be improved by incorporating the changes in one carbon metabolism produced by phenobarbitone.
Lockwood
G F
GF
Department of Drug Metabolism and Pharmacokinetics, Smith Kline and French Research Ltd, Welwyn, UK.
Chenery
R J
RJ
Oldham
H G
HG
Standring
P
P
Norman
S J
SJ
D000818:Animals; D000983:Antipyrine / Q000378:metabolism*; D001944:Breath Tests; D002245:Carbon Dioxide / Q000032:analysis; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D008297:Male; D008433:Mathematics; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010634:Phenobarbital / Q000494:pharmacology; D011865:Radioisotope Dilution Technique; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D002250:Carbon Radioisotopes; D002245:Carbon Dioxide; D003577:Cytochrome P-450 Enzyme System; D000983:Antipyrine; D010634:Phenobarbital