5-AMINOLEVULINIC ACID-INDUCED PROTOPORPHYRIN-IX ACCUMULATION IN TISSUES - PHARMACOKINETICS AFTER ORAL OR INTRAVENOUS ADMINISTRATION

In this study, the biodistribution of 5-aminolaevulinic acid (ALA) and accumulation of protoporphyrin IX (PpIX) in rats have been examined. Two groups of 21 WAG/Rij rats are given 200 mg/kg ALA orally or intrav enously. Six rats serve as controls. At 1, 2, 3, 4, 6, 12 and 24 h aft er ALA administration, ALA and porphyrin concentrations are measured i n 18 tissues and fluids. Liver enzymes and renal-function tests are me asured to determine ALA toxicity. In both groups ALA concentration is highest in kidney, bladder and urine. After oral administration, high concentrations are also found in duodenal aspirate and jejunum. Mild, short-lasting elevation of creatinine is seen in both treatment groups . Porphyrins, especially PpIX, accumulate mainly in duodenal aspirate, jejunum,liver and kidney (> 10 nmol/g tissue), less in oesophagus, st omach, colon, spleen, bladder, heart, lung and nerve (2-10 nmol/g tiss ue), and only slightly in plasma, muscle, fat, skin and brain (< 2 nmo l/g tissue). In situ synthesis of porphyrins rather than enterohepatic circulation contributes to the PpIX accumulation. Confocal laser scan ning microscopy shows selective porphyrin fluorescence in epithelial l ayers. Peak levels and total production of porphyrins are equal after oral and intravenous ALA administration. In conclusion: administration of 200 mg/kg ALA results in accumulation of photosensitive concentrat ions of PpIX, 1 to 6 h after ALA administration, in all tissues except muscle, fat, skin and brain. Knowledge of the time-concentration rela tionship should be helpful in selecting dosages, routes of administrat ion and timing of ALA photodynamic therapy. (C) 1998 Elsevier Science S.A. All rights reserved.