Use of TIN Protoporphyrin to Suppress Severe Recurrent Acute Attacks of Porphyria
Haem Oxygenase Inhibitors: Theoretical Background
Since haem is catabolised by the enzyme haem oxygenase, itself induced by haem, the use of haem oxygenase inhibitors to maintain haem levels has been mooted. A number of substituted metalloporphyrins will inhibit haem oxygenase; these include tin protoporphyrin, tin mesoporphyrin and zinc mesoporphyrin. Tin protoporphyrin markedly inhibits the induction of hepatic ALAS by allylisopropamide in adults rats; a dose of 50 µmol/kg body weight resulting in a 60% reduction in ALAS activity. This is accompanied by a decrease in the urinary excretion of ALA and PBG. At the highest dose, excretion was totally abolished (Galbraith et al 1985). In normal volunteers, administration of tin protoporphyrin results in a mean 38% decrease in serum bilirubin and a mean 47% decrease in biliary bilirubin (Berglund et al 1988). This is accompanied by an increased excretion of endogenous haem in bile for 48 hours. Tin protoporphyrin is rapidly cleared from plasma with a half-life of 3.4 hours though the inhibition of haem oxygenase lasts for at least four days. The activity of microsomal haem oxygenase has been measured directly in liver samples and has shown to be diminished by tin protoporphyrin (Berglund et al 1988). This work has been extended to experimental studies in patients with acute porphyrias. Administration of both tin protoporphyrin and tin mesoporphyrin, whose potency in vivo is approximately 5 to 10 times greater (Drummond 1987), led to significant decreases in urinary ALA and porphyrin excretion in patients with AIP and VP (Galbraith and Kappas 1989). Experience has shown that tin protoporphyrin alone is of no value in reducing ALA and PBG excretion in patients with the acute attack (Dover et al 1993). Furthermore, the combination of haem arginate and tin protoporphyrin was no more effective than haem arginate alone in reducing ALA and PBG excretion in an attack but there was evidence that tin protoporphyrin prolonged the biochemical remission induced by haem arginate.
We have accumulated some experience in the use of tin protoporphyrin. We believe it to be effective in maintaining the efficacy of haem arginate in the face of frequent dosing which, in our experience, may lead to the development of tolerance and consequent therapeutic failure. In contrast to the experience of Dover et al (1993), we have found no evidence that the attack-free interval is significantly prolonged by its use. A further observation is with regard to its safety. Despite the administration of as many as 120 doses of 25 µg, there has been no clinical evidence of toxicity. When two patients were on two occasions inadvertently exposed to sunshine within 48 hours of administration, marked skin erythema was noted in sun-exposed areas. Cumulative darkening of the skin was also noted over time. We have however noted the appearance of apparent iron overload and the accumulation of an unusual pigment, which may represent tin, in the livers (at autopsy) of both patients who received large amounts of haem arginate and tin protoporphyrin. Definitive identification of this pigment is awaited.
Dose and Administration
The dose recommended to us by Dr Michael Moore was 1 mmol/kg/day for 3 days. We have however used a standard regimen of 25 mmol by slow bolus IV injection, given on days 1, 2 and 3 of a 4-day course of daily haem arginate 5 ml in 100 ml 20% human serum albumin.
We have thus always combined tin protoporphyrin with haem arginate administration. In our experience with a handful of patients with fortnightly recurrent acute attacks of AIP, tin protoporphyrin was not required with every course of haem arginate, but in practice seemed to confer benefit when combined with every second course.
Our indications therefore were:
- A severe attack with no clinical improvement following four days of haem arginate. In this case haem arginate was administered for a further four days, combined with three doses of tin protoporphyrin.
- In patients with a pattern of recurrent acute attacks with poor response to haem arginate, co-administration of tin protoporphyrin with haem arginate for every second course of haem arginate.
Treatment with tin protoporphyrin must be seen as desperate therapy given only in the face of severe, recurrent attacks failing to respond to standard haem arginate therapy and should be considered only by those with extensive experience in the management of acute attacks.
Preparation of Tin Protoporphyrin For Injection
Tin proto, Sn(IV) protoporphyrin dihydrochloride, may be ordered from:
Frontier Scientific, Inc
Catalogue number is Sn 749-9
Unit sizes: 250 mg, 1 g.
(With acknowledgements to Prof Michael Moore)
- Make a buffer of one of the following:
· 0.2M trisodium orthophosphate (4.127 g in 54.3 ml distilled water)
· 0.2M disodium hydrogen orthophosphate (2.84 g in 100 ml distilled water).
- Dissolve tin proto 101.7 mg in 5.4 ml buffer.
- Add 15 ml distilled water.
- Add 1M HCl, titrating against pH until pH=7.5 - 7.8.
- Make up to a final volume of 27 ml with distilled water.
- Filter through a 2 mm bacteriological filter to sterilise. Dispense into 5 ml dark ampoules and seal. Store in the dark; do not refrigerate as the tin protoporphyrin tends to precipitate in the cold.
- This yields a final concentration of 3.8 g/l or 5 mM, and each 5 ml aliquot contains 25 mmol tin proto. It can safely be stored for several months.
- Berglund L, Angelin B, Blomstrand R, Drummond GH, Kappas A (1988). SN-protoporphyrin lowers serum bilirubin levels, decreases biliary bilirubin output, enhances biliary heme excretion and potently inhibits hepatic heme oxygenase in normal human subjects. Hepatology 8:625-31.
- Dover SB, Moore MR, Fitzsimmons EJ, Graham A, McColl KE (1993). Tin protoporphyrin prolongs the biochemical remission produced by heme arginate in acute hepatic porphyria. Gastroenterology 105:500-6.
- Drummond GS (1987). Control of heme metabolism by synthetic metalloporphyrins. Ann NY Acad Sci 514:87-95.
- Galbraith RA, Drummond GS, Kappas A (1985). Sn-protoporphyrin suppresses chemically induced experimental hepatic porphyria. Potential clinical implications. J Clin Invest 76:2436-9.
- Galbraith RA, Kappas A (1989). Pharmacokinetics of tin-mesoporphyrin in man and the effects of tin-chelated porphyrins on hyperexcretion of heme pathway precursors in patients with acute inducible porphyria. Hepatology 9:882-8.