The pharmacokinetics of pentaerythritol tetranitrate (2,2-bis(hydroxymethyl)-1,3-propanediol tetranitrate, 1) were studied in rats following a single intra-arterial or oral dose (2 mg/kg) of the 14C-labeled drug. Blood levels of the tetranitrate and its metabolites were determined using a thin-layer radiochromatographic procedure. The apparent systemic clearance of 1 was 0.61 +/- 0.16 L/min/kg (mean +/- SD, n = 6) which exceeded the value of normal cardiac output in rats. The steady-state volume of distribution was 4.2 +/- 1.1 L/kg (n = 6), and the elimination half-life was estimated at 5.8 +/- 0.6 min (n = 6). Blood levels of 1 were only detectable (higher than 4.0 ng/mL) in three of the six rats examined after the oral dose. The trinitrate derivative (2,2-bis(hydroxymethyl)-1,3-propanediol trinitrate, 2) the active metabolite of 1, was not detectable following oral dosing with the tetranitrate. The oral bioavailability of 1 was in the range of 0-8%. In spite of the low water solubility of 1 (i.e., 1 microgram/mL), a rather high fraction of the radioactive oral dose [25.7 +/- 10.3% (n = 4) versus 62.4 +/- 14.5% (n = 4) from the intra-arterial dose] was recovered in the urine. A significant portion of the intra-arterial dose (32.7 +/- 11.0%, n = 4) was eliminated in feces, indicating enterohepatic recycling of radioactivity. Analysis of the metabolite pattern in urine indicated extensive metabolism of 1, 2, and the dinitrate derivative 3 (2,2-bis(hydroxymethyl)-1,3-propanediol dinitrate). Less than 0.2% of the dose was recovered as unchanged drug and 2 following either route of administration.