George T. Okita

Studies on the Renal Excretion of Radioactive Digitoxin in Human Subjects with Cardiac Failure

Randomly labeled C14-digitoxin was used in a quantitative study of the renal excretion of unchanged digitoxin and its metabolites in three human subjects with cardiac insufficiency. The elimination of approximately 60 to 80 per cent of an administered dose through the kidney suggests that the major route of elimination of digitoxin in cardiac patients is through the urinary route. There is a marked initial excretion of digitoxin during the first two days after administration of the radioactive drug followed by a gradual leveling off of the excretion gradient thereafter. Minute amounts of unchanged digitoxin have been detected in the urine up to the fortieth day after administration of a single dose of the glycoside, while C14-labeled compounds were detected up to the seventy-fourth day.

Brain cholesterol: biosynthesis with selected precursors in vivo.

OUR previous studies (KABARA et al., 1957,1958) on the biosynthesis and metabolism of cholesterol revealed that certain precursors were incorporated into the brain cholesterol of adult mice. Prior to these findings other workers reported low or almost undectable rates of lipid metabolism in the brain of adult animals (ROSSITER, 1957; MCILWAM et ul., 1959). More recent studies have suggested that the adult mouse brain can synthesize cholesterol in vivo when the route of precursor administration is either intracisternal (MCMILLAN et ul., 1957) or intracerebral (NICHOLAS and THOMAS, 1959). However, only a small amount of incorporation was detected when precursors were administered intraperitoneally. In our initial studies on the in vivo incorporation of precursors into brain sterol we employed the intraperitoneal route of injection. Since our data appeared to differ from the results obtained by others, a more detailed investigation of our initial findings (KABARA and OKITA, 1959) was carried out.

Placental Transfer of Radioactive Digitoxin in Pregnant Women and its Fetal Distribution

Placental transfer of radioactive C14-digitoxin was investigated in four pregnant women. The concentration of the labeled drug and its metabolic products in the various fetal organs was determined. Less than 1 per cent of the administered glycoside was detected in the fetus as unchanged digitoxin and less than 3.5 per cent as its metabolites. The fetal heart and kidney of 11 to 12 weeks gestation had the highest concentrations. However, at near term the fetal liver, gallbladder and intestine had somewhat similar concentrations. Metabolic conversion of the cardiac glycoside by fetal liver as well as biliary excretion is indicated from the tissue distribution data.

STUDIES WITH RADIOACTIVE DIGITALIS

The cardiac glycosides have probably been investigated more extensively than any other group of drugs and we have a fairly complete and accurate picture of their circulatory effects. However, to date, the body of knowledge concerning the metabolic fate of digitalis in man is very limited. With the availability of isotopically labeled C14-digitoxin it has been possible to overcome some of the difficulties encountered by earlier investigators in measuring microgram quantities or less of the cardiac glycoside in body tissue. The purpose of this communication is to summarize our findings on the blood level, tissue distribution, excretion and placental transfer of radioactive digitoxin in human subjects.

PENETRATION OF ATP INTO THE MYOCARDIUM.

Summary When the isolated guinea pig heart is perfused with C14- and P32-labeled ATP of known isotope ratio, ATP isolated from the myocardium shows an isotope ratio 100 times greater than the starting material. Inorganic P32 is liberated into the perfusion fluid along with C14-labeled dephosphorylation and deamination products of ATP. UTP, GTP, CTP and ITP are also dephosphorylated when perfused. The results indicate that the ATP molecule does not enter the myocardium as such, but first is degraded and later resynthesized intracellularly.

Continuous measurement of specific activity of C14O2 in expired air

Abstract The majority of carbon compounds of metabolic interest ultimately are degraded to carbon dioxide and urea which are excreted. Following the administration of a tracer dose of a C14-labeled metabolite, there is assumed to be a pattern of elimination of C14O2 which is characteristic for the healthy state, and which is distorted in disease. This pattern is represented by the time-course of specific activity of C14O2 in expired air. Metabolic studies in human subjects and in animals are facilitated by the apparatus described in this report which permits the continuous measurement of radioactive C14O2 in expired air. The apparatus consists of an air-collection system, a ventilation meter, a C12O2 (infrared) analyzer, a 4π G-M counter with anti-coincidence circuitry, and a ratio analyzer to compute C14/C12. Analog data are printed out on a four-channel recording millivoltmeter at the rate of four items per minute on each channel. The data are in such a form that they can be converted readily to digital information for processing in a high-speed computer. Rapid estimates of the size and kinetics of the carbon dioxide pool are possible when labeled bicarbonate is used as the tracer.

Placental transfer of radioactive digitoxin in rats and guinea pigs.

Summary 1. Digitoxin, and possibly its metabolic products, crosses the placenta of rats and guinea pigs. 2. Larger amounts of both unchanged digitoxin and its metabolites were found in the fetuses of guinea pigs than in the fetuses of rats. 3. Embryonic tissue may have a marked ability to catabolize the drug, or there may be a selective penetration of the metabolites across the placenta, as noted by its high metabolite-digitoxin ratio. 4. On a tissue weight basis, digitoxin and its metabolites were found in higher concentrations in the embryonic heart than in the maternal heart.