Anderson KE, Kormos-Hallberg C
University of Texas Medical Branch, Galveston, TX, USA
In acute intermittent porphyria (AIP) hepatic δ-aminolevulinic acid (ALA) synthase is induced and levels of the heme precursors ALA, porphobilinogen (PBG) and porphyrins are increased. Intravenous heme therapy represses hepatic ALA synthase and promptly reduces ALA, PBG and porphyrin excretion. Previous studies suggest that tin mesoporphyrin (SnMP), a potent inhibitor of hepatic heme oxygenase, may potentiate the effects of heme therapy during acute attacks by inhibiting its breakdown. Dose-ranging and pharmacokinetic observations are lacking, and are most feasible in asymptomatic patients. Asymptomatic patients with documented AIP and persistently increased levels of heme precursors, were enrolled in a dose-ranging study of single doses of intravenous heme (heme arginate or heme albumin, 1.0 or 3.0 mg/kg body weight) immediately preceded by SnMP, either 0, 0.5 or 1.0 mmol/kg. Serum PBG, urine ALA, PBG and porphyrins, and plasma heme and SnMP levels were measured up to 72 h. Following results were obtained: (1) Plasma levels of heme and SnMP were dose-dependent and followed first-order kinetics. (2) SnMP 1.0 mmol/kg prolonged the half-life (t1/2) and decreased clearance (Cl) of heme given at the 1.0 mg/kg dose (t1/2 10.2±2.2 h vs. 13.8±2.8 h, p=0.035; Cl 202.9±13.4 vs. 135.6±30.4 mL/h, p=0.0014). Effects with heme 3 mg/kg, and effects of SnMP 0.5 mmol/kg with either dose of heme did not reach statistical significance. (3) Decreases in heme precursors induced by heme were strongly dose dependent. (4) An additive effect of both doses of SnMP was evident with heme 3 mg/kg, but not 1 mg/kg, achieving statistical significance on day 3. Change from baseline in plasma PBG 72 h after heme 3 mg/kg was –17.8±14.8, and after heme and SnMP, either 0.5 or 10 mmol/kg was –60.5±32.5 (p=0.05) or 61.9±15.8% (p=0.03), respectively. Corresponding changes in urinary PBG on day 3 were –20.8±46.6 mg/day with heme alone, and –75.3±12.6 (p=0.01) and –88.0±0.6 (p=0.001) mg/day with heme and SnMP 0.5 and 10 mmol/kg, respectively. Mild, dose-related photosensitivity was a common and expected side effect. In conclusion, SnMP follows first-order, dose-dependent kinetics in AIP, prolongs the metabolic clearance of intravenous heme and enhances its biochemical effects. SnMP may be beneficial as adjunctive therapy in AIP, especially for prolonging the effects of heme therapy. [G Drummond and A Kappas, Rockefeller University, New York, NY provided SnMP. Supported in part by grants from US FDA (FD-R-001459), American Porphyria Foundation and NCRR/NIH (MO1 RR-00073).]