The effect on the hepatic elimination rate of drug bound to erythrocytes and to albumin was compared with harmol, a relatively hydrophilic drug of high hepatic intrinsic clearance, in the single-pass isolated perfused rat liver preparation (n = 12). The steady-state hepatic extraction ratio (E) of harmol (50 microM) was measured during three consecutive 35-min periods with three different perfusates: Krebs-Henseleit buffer, buffer containing bovine serum albumin (2%), and buffer containing washed human erythrocytes (10%) perfused at 5 mL/min/g liver in randomized order. The mean unbound fraction (fu) of harmol in the latter two perfusates was 0.55 +/- 0.07 and 0.62 +/- 0.08, respectively, and the mean E for the three perfusates were 0.85 +/- 0.06, 0.62 +/- 0.07, and 0.71 +/- 0.08, respectively. The sinusoidal model fitted the relationship between E and fu better than the venous equilibrium model. Four further experiments, with perfusates of buffer, buffer + 2% albumin, and buffer + 4% albumin, confirmed that harmol elimination conformed to the sinusoidal model. For each of the 12 experiments that used erythrocyte perfusate, E and fu data from each of the two non-erythrocyte perfusates were used to predict E for the erythrocyte perfusate at the observed fu of 0.62, with the sinusoidal model. There was no significant difference between the observed (0.71 +/- 0.08) and predicted (0.68 +/- 0.10) E values (p > 0.05). This result suggests that release of harmol from erythrocytes is not a rate-limiting factor in the hepatic elimination of harmol, and that plasma membrane permeability does not contribute readily to a red cell carriage effect, at least with moderately polar and small molecules.
Investigations concerning the stability of a group of factors contained in cod liver residue and displaying vitamin B12 activity have led to the conclusion that under the conditions prevailing during the rendering process, as developed at the Atlantic Fisheries Experimental Station, little or no deactivation occurs. This is in sharp contrast with what occurs under more drastic conditions such as used in the alkali-digestion process.The study of the microbiological method used for the determination of vitamin B12 activity has shown that one step of the analytical procedure, namely, that phase during which the extraction of the sample is performed, is responsible for anomalous results. Deactivation occurs during this stage to an extent which varies according to the previous history of the material. The addition of thioglycolic acid or ascorbic acid during this period does not effectively protect the material unless culture medium is added as well. Medium alone is inefficient. Sodium bisulphite on the other hand exerts protection even in the absence of medium. This effect of sodium bisulphite applies not only to cod liver residue, but also to materials of diverse origin, mammalian viscera included. The data obtained show that vitamin B12 itself is not involved; presumably vitamin B12a and vitamin B12b are, although there is no direct evidence of their presence in cod liver.As a protection during extraction, 0.08 per cent to 0.1 per cent of sodium bisulphite calculated on the amount of wet material appeared to be optimum.
Extracts and enzymic hydrolysates were prepared from cod, haddock, salmon, whale, seal, beef and pork livers. Extraciion was carried out with water at pH 5; enzymic hydrolysis was ellected by papain at pH 5.5 and at 65'C. followed by pancreatin at pI{ 7.5 and at 50"c. The proper digestlon times were established. Extracts, as well as hydr_olysates, were concentratei by distiilation in aacuo to the consistency of syrup and then dried at a low temperature in oacuo. The preparations were analysed for a large number of inorganic and organic constituents. Compariions of the results for preparations from fish livers with corresponding products from inammalian livers lead to thelonclusion that fish livers are useful raw materials ior the production of extracts and enzymic hydroiysates for use in foods or in medicinal preparations.
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