A [14C]phenacetin breath test to measure hepatic function in man

Phenacetin, a high-clearance drug, was labeled as [14C-ethyl]phenacetin and used in a breath test of hepatic function. 14CO2 appeared rapidly in breath such that more than 30% of the administered radioactivity was expired in 2 hr. For all means of expression used to describe the appearance of 14CO2 in breath, normal controls and hospitalized patients without liver disease were clearly separated from cirrhotic subjects with moderate and severe liver damage. The phenacetin breath test was validated by the close correlation of 14CO2 appearance with the disposition of the parent compound examined after its intravenous administration, and by demonstration that the rate-limiting step in 14CO2 generation from labeled phenacetin occurred proximal to 14CO2 generation from [14C]acetate given intravenously. Correcting for the actual volume of CO2 exhaled by control and cirrhotic subjects did not increase the sensitivity of the test. The phenacetin breath test has potential as a simple procedure to quantitate hepatic metabolism of drugs, particularly those mediated by cytochrome P448.