Pharmacokinetics of pentaerythritol tetranitrate following intra‐arterial and oral dosing in the rat

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 μg/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 intraarterial 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.