Using a modified HPLC method with a fluorescence spectrophotometer and a weak cation exchanger, it was possible to separate (R)-alpha-methylhistamine (alpha-methylhistamine) from histamine in plasma and various tissues. The assay was used to study the disposition and pharmacokinetic analysis of alpha-methylhistamine after a bolus intravenous administration to rats. After rapid intravenous administration (12.6 mg kg-1), the plasma concentration declined biexponentially with a half-life of 1.3 min in the elimination phase. The area under the plasma concentration-time curve and total body clearance were 130 micrograms min mL-1 and 97 mL min-1 kg-1, respectively. After administration, alpha-methylhistamine was immediately transferred to various tissues. The concentration was high in the kidney, lung, and liver (kidney > lung > liver), but low in the brain. The tissue-to-plasma concentration ratios in peripheral tissues were greater than 1, suggesting that the transfer of alpha-methylhistamine to peripheral tissues was due to a specialized transport mechanism or possibly to tissue binding. However, the finding that the tissue/plasma ratio in the brain was lower than unity suggests that the transport system in this tissue depends on a concentration gradient, and that alpha-methylhistamine crosses the blood-brain barrier in rats with difficulty.