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Intra- and Interindividual Variability in Systemic Exposure in Humans to 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline and 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, Carcinogens Present in Cooked Beef¹

Department of Clinical Pharmacology, Royal Postgraduate Medical School, Ducane Road, London W12 0NN, United Kingdom [A. M. L., A. R. B., N. J. G., D. S. D., S. M.], and Biomedical and Environmental Sciences Divisions, Lawrence Livermore National Laboratory, Livermore, California 94550 [M. G. K.]

During the cooking of beef, the genotoxic heterocyclic aromatic amines 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) are formed. Little is known about the fate of these compounds in humans or the factors affecting it. We have developed assays based on capillary column gas chromatography-negative ion mass spectrometry capable of the simultaneous measurement of MeIQx, DiMeIQx, and PhIP in cooked meat and in human urine using stable isotope labeled analogues. Ten normal, healthy male volunteers were invited to consume a standard cooked meat meal (400–450 g lean beef, cooked as patties on a griddle hotplate) on four separate occasions over a period of 14 months. Following consumption of the test meals, urine was collected from 0 to 8 h, during which time all free amines were excreted and analyzed for MeIQx, DiMeIQx, and PhIP. Subjects ingested 240 ± 9 (SEM) g cooked meat, which contained 2.2 ± 0.2 ng MeIQx/g meat, 0.7 ± 0.1 ng DiMeIQx/g meat, and 16.4 ± 2.1 ng PhIP/g meat. The variability in relative systemic bioavailability was assessed from the percentage of ingested amine excreted unchanged in the urine. Subjects excreted 2.1 ± 1.1% of MeIQx and 1.1 ± 0.5% of PhIP ingested as unchanged amine in the urine. Levels of DiMeIQx in urine, if present, were below the sensitivity of our assay (20 pg/ml) and could not be detected in any of the samples analyzed. Irrespective of dose, urinary excretion of unchanged MeIQx or PhIP (expressed as a percentage of the ingested dose) remained constant for each individual subject. The intrain-dividual coefficients of variation for MeIQx (28.4%) and PhIP (23.7%) were low and the pooled interday (intrasubject) coefficients of variation for both compounds were only 19 and 3.4%, respectively. In contrast, intersubject (intraday) variation was greater, with pooled coefficients of variation of 145% for MeIQx and 71% for PhIP. Based on these studies, it should be possible to use the percentage excretion of MeIQx and PhIP to assess the relative bioavailability of these compounds in humans.

¹ Work carried out at the Royal Postgraduate Medical School was supported by grants awarded by the National Cancer Institute, Department of Health and Human Services (USPHS Grant CA40895-02), Ministry of Agriculture, Fisheries and Food, and the Cancer Research Campaign. Work at the Lawrence Livermore National Laboratory was performed under the auspices of the United States DOE under contract W-7405-ENG-48 and supported by National Institute for Environmental Health Sciences Agreement 22YO1-ES-10063 and National Cancer Institute Grant RO1-CA40811.

² To whom requests for reprints should be addressed.

Received 4/27/92. Accepted 9/11/92.

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