Gastrointestinal and hepatic first-pass effects of salicylamide in rats.
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Biomedical subjects
Publications and source records attributed to K Iwamoto.
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To evaluate the disposition of fractionated 3H-heparin, high affinity fraction (fraction A) and low affinity fraction (fraction NA) to protamine were prepared in this study from commercial 3H-heparin by affinity chromatography on protamine-Sepharose and gel filtration chromatography. Following intravenous administration of fraction A to rats, it seemed that the radioactivity in plasma declined one-exponentially with time to a pseudo-steady-state level, and 20.5% of dose was excreted in urine in 5 h. However, following the administration of fraction NA to rats, the plasma radioactivity curve was different from that of fraction A, and 69.8% of dose was excreted in urine in 5 h. It was found that fraction A and fraction NA had the distinctly different disposition characteristics in the body. Additionally, whole-body autoradiography with fraction A showed that the liver, bone marrow, kidney cortex, salivary gland and intestine played an important role in the distribution of it. It was suggested by gel filtration chromatography and affinity chromatography that the main material of the radioactivity excreted in urine in 5 h has the same properties as that of the administered heparin fraction.
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The method of estimating gestational age (GA) was studied in each trimester. CRL, BPD and FFL were selected as the parameters of ultrasonic B-mode measurement, and each standard curve was recorded. The less erroneous range on each parameter was decided. The range of CRL was from 20 to 80mm, that of BPD from 20 to 70 mm and that of FFL from 20 to 55mm. Within these ranges, GA estimated by CRL showed 2.9 days difference on average compared to the GA determined by LMP, compared with BPD 4.6 days and with FFL 4.9 days. CRL was the most accurate, but that with BPD or FFL could be useful in the 2nd trimester. Since the difference in the growth of each fetus would become apparent in late stage, the ranges of GA for each measured value of BPD or FFL were determined in the 3rd trimester by the mean +/- 3/2 SD for GA determined by CRL. Since 67 to 100% of the studied cases were included in the ranges of GA, the estimation will be useful in the 3rd trimester. FFL is more useful than BPD in the 3rd trimester, and it is also utilized in cases where BPD measurement is not possible due to fetal head descent.
To understand the role of omega-cyclohexyl fatty acid residue of lipids in acido-thermophilic bacterial membranes, three unusual phosphatidylcholines, 1, 2-di-11-cyclohexylundecanoyl-L-alpha-phosphatidylcholine (11CYPC), 1,2-di-13-cyclohexyltridecanoyl-L-alpha-phosphatidylcholine (13CYPc), and 1-13-cyclohexyltridecanoyl-2-11-cyclohexylundecanoyl-L-alpha- phosphatidylcholine (1-13CY-2-11CYPC) were prepared and the steady-state fluorescence anisotropy of 1, 6-diphenylhexatriene (DPH) in the hydrophobic domain of these liposomal bilayers was determined. Compared with the case of dipalmitoyl (DPPC) or dimyristoyl phosphatidylcholine (DMPC), introducing the omega-cyclohexyl moiety onto lecithins makes the bilayers fluid below the phase transition temperature, while immobilizes them above the phase transition temperatures. The properties of the unusual phosphatidylcholine liposomes suggested by the steady-state fluorescence anisotropy investigation were in good agreement with those obtained from the thermotropic and permeability investigations. Results obtained are discussed from the view point of the role and function of lipid membranes of acido-thermophilic bacteria which contain unusual fatty acids.
Under specific conditions where neither induced aggregation nor fusion is brought about, the adsorption of polysaccharides on liposomal membranes was investigated by the fluorescence depolarization technique using fluoresceinylthiocarbamoyl-dextrans (FITC-dex) as probes. The adsorption of FITC-dex on liposomes significantly increased the fluorescence polarization of FITC fluorophore due to the restriction of the mobility of the dextrans. Dextran with larger molecular weight was efficiently adsorbed on liposomes, in good agreement with the tendency for polysaccharide-induced aggregation of liposomes (Sunamoto et al. (1980) J. Biochem. 88, 1219--1226). The adsorption seemed to be related to the fluidity of liposomal membranes, since dextrans were adsorbed more efficiently on egg lecithin liposomes than dipalmitoyl lecithin liposomes at 25.0 degrees C. However, the adsorption of dextrans did not cause a significant change in the fluidity of the liposomal membrane itself under the specific conditions adopted in this work; this was ascertained from the mobility of sodium 8-anilino-1-naphthalenesulfonate (ANS) intercalated close to the surface of liposomes.
The first-pass effect of aspirin was measured in male Wistar rats by comparing the plasma concentration after intravenous, oral or intraportal administration (10 mg kg-1) of the drug. Approximately 88 and 86% of the dose was excreted mostly as salicylic acid and its conjugated forms, glucuronide and sulphate, in urine within 48 h of i.v. or oral administration, respectively. This suggests that the gastrointestinal absorption of aspirin was essentially complete in rats. On the average, the area under the plasma concentration-time curve for unchanged aspirin following oral dosing (AUCo) was 0.35 of that obtained following i.v. administration (AUCi.v.) and 0.53 of that following intraportal administration (AUCp). Therefore, orally administered aspirin is subject to first-pass metabolism both in the gut and in the liver of rats. The gastrointestinal first-pass effect is estimated to be relatively more important than the hepatic effect.
The absorption, distribution and elimination of creatinine and urea, which are considered to pass through the water-filled pores of biological membranes easily, were investigated in hyperthyroid mice to clarify the effects of enhanced blood circulation rate on drug behaviour in the body. The elimination rate constant in hyperthyroid mice was significantly and considerably larger than that in the control in both creatinine and urea (p less than 0.01). This result might be based on the increased urinary excretion rate of these two chemicals in hyperthyroid mice. The result of autoradiographic study indicated that creatinine was distributed more homogeneously in hyperthyroid mice than the control at 30 s and 2 min following intravenous administration. It was probably caused by the enhanced membrane permeability to creatinine due to some physiological changes (e.g. blood flow rate and pressure) or to a change of membrane itself. The gastrointestinal absorption of these two chemicals were also evaluated by the expiratory excretion of 14CO2 following oral administration. The results suggested that creatinine might be absorbed more slowly in hyperthyroid mice than in the control, and that in the case of urea such a difference in absorption might not exist.
To evaluate the distribution of water soluble macromolecular compound in the body, heparin was selected as one of the model compounds. Urinary and fecal excretion, and plasma levels following intravenous administration of commercial 3H-heparin were investigated at three different dose levels. Whole-body autoradiography was also carried out periodically following intravenous administration of 3H-heparin at single dose level. The distribution of radioactivity following the administration of 3H-heparin was compared with that of 14C-polyethylene glycol 6000. The statistically significant but only very small differences in the pharmacokinetic parameters and in the urinary excretion were observed over the wide range of dose (0.20, 2.0 and 20 mg/kg). The decline of plasma radioactivity following the administration of 3H-heparin appeared to be biexponential with time and pharmacokinetic constants were calculated according to a two-compartment open model. Whole-body autoradiograms showed that the reticulo-endotherial system (R.E.S.) may play an important role in removal of the radioactivity of heparin from the circulating blood.
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Ultrasonographic measurements of fetal limb bones were studied in the cases ranged from 15 to 41 weeks of gestation. The growths of BPD, fetal femur length (FFL) and fetal humerus length (FHL) were studied, though some cases showed the difficulty in fetal biparietal diameter (BPD) measurement due to either engagement into the pelvis or rotation of fetal head. Correlation between BPD ad FFL or FHL was also evaluated. 1) Both FFL and FHL showed linear growth patterns during 16 to 40 weeks of gestation. The correlation equation; Y = 0.20X - 0.85 (R = 0.99) was obtained where X was gestational age and Y was FFL. In another equation, Y = 0.16X - 0.28 (R = 0.99) when Y was FHL. These equations showed the increment of FFL and FHL are 2.0mm and 1.6mm per a week respectively. 2) Correlation coefficients between BPD and FFL or FHL were as high as 0.97 and 0.98 respectively. 3) Comparison of in vivo ultrasonic and postnatal radiographic measurements of the femur bone of an autopsied stillbirth infant showed that the ultrasonically measured FFL corresponded to the length of ossified part of the bone. 4) Both FFL and FHL were evaluated as useful as BPD for the estimation of gestation age.