Association between the membrane-fluidizing properties and porphyrin-inducing activity of alfaxolone and related steroids.
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Biomedical subjects
Publications and source records attributed to G S Marks.
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Drug-induced porphyrin accumulation occurs in chick embryo liver cells maintained in serum-free Waymouth MD 705/1 medium. Addition of insulin and thyroxine to the medium results in a marked enhancement of porphyrin accumulation. The addition of hydrocortisone results in a further enhancement of porphyrine accumulation. Several agents which are reported to increase intracellular adenosine 3':5'-monophosphate (cAMP) levels, viz. glucagon, sodium fluoride, cAMP or its dibutyryl derivative, 3-isobutyl-1-methylxanthine and papaverine enhanced drug-induced porphyrin biosynthesis. On the other have, agents which are reported to decrease intra-cellular cAMP levels, viz. alloxan and imidazole, diminished drug-induced porphyrin accumulation. cAMP appears to enhance, but not to function as a "second messenger" in drug-induced porphyrin biosynthesis. Drug-induced porphyrin accumulation in chick embryo liver cells depend upon the insulin to glucagon ratio. A low level of porphyrin accumulation occurs at insulin to glucagon ratios similar to those found following glucose administration in vivo, suggesting a possible explanation for the therapeutic effect of glucose in hepatic porphyria. The 5 alpha A(A:B trans) and 5 beta H(A:Bcis) steroids are equipotent in inducing delta-aminolevulinic acid synthetase and porphyrin accumulation in chick embryo liver cells maintained in serum-free culture medium. Thus, there is no specific steric requirement for porphyrin-inducing activity in steroids.
The two steroid components of Alfathesin, alfaxolone and alfadolone acetate, have been tested for porphyrin-inducing activity in chick embryo liver cell culture and for hepatic ALA-synthetase-inducing activity in the 17-day-old chick embryo. In cell culture alfoxolone was shown to have potency comparable to that of thiopental, while alfadolone acetate had low potency. In the 17-day-old chick embryo alfaxolone has a third the potency of thiopental; alfadolone acetate showed low potency. The authors conclude that an induction dose of Alfathesin would be less likely than a comparable dose of thiopental to increase ALA-synthetase activity in a patient with hereditary hepatic porphyria.
Pharmacokinetic analysis of nitroglycerin (GTN) has been hampered by the lack of a sensitive and specific method for measuring GTN in blood. Therefore, we examined the appearance of GTN in blood after administering 0.6 mg sublingually in 10 studies of normal volunteers. We used a gas-liquid chromatographic method with electron-capture detection and isosorbide dinitrate as the internal standard. GTN appeared in blood at 0.5 minutes, reached a peak of 2.3 +/- 0.36 ng/ml at 2 minutes, fell to 50% of peak value at 7.5 minutes and was barely detectable at 20 minutes. These blood levels paralleled the changes in heart rate and systolic blood pressure. These data show rapid appearance and disappearance of GTN from blood after sublingual administration, a large volume of distribution, and a rapid rate of total body clearance that precludes the liver from being the sole elimination site. This method for analysis of GTN and isosorbide dinitrate should be helpful in defining the role of chronic nitrate therapy.
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The 5alphaH (A : B trans) and 5betaH (A : B cis) steroids are equipotent in inducing delta-aminolevulinic acid synthetase and porphyrin accumulation in chick embryo liver cells maintained in serum-free culture medium. Thus there is no specific steric requirement for porphyrin-inducing activity in steroids.
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