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14C-Fluphenazine base was administered intramuscularly in sesame oil to five male beagles (2 mg/kg). The concentration of radioactivity in plasma and the excretion of radioactivity in urine and feces were measured for 14 days. Maximum concentrations of radioactivity were found in plasma 2 hr after administration. These levels declined with elimination half-lives of 3.20 hr during the 2-12-hr interval after dosing and of 4.02 days during the 2-14-day interval. Most administered radioactivity was excreted during the first 2 days after dosing, predominantly in the feces. An average of 0.43% of the dose was present at the injection site 14 days after dosing; some residual radioactivity was found in the liver and in the ocular portion consisting of the combined retina, choroid, and sclera. 14C-Fluphenazine and its enanthate and decanoate esters were each administered intravenously to three different groups of intact dogs at doses of 1 mg/kg. Regardless of which compound was administered, concentrations of radioactivity in the plasma of these dogs were comparable. Thirty minutes after these dogs had been dosed with 14C-fluphenazine enanthate or 14C-fluphenazine decanoate, most radioactivity in the plasma was present as 14C-fluphenazine base and other unidentified metabolites; at this time, at least 79% of either of the two 14C-fluphenazine esters had been biotransformed. The excretion of radioactivity by these same three groups of dogs was very similar, regardless of which of the compounds was given. In 7 days, an average of only 3-4% of the dose was excreted in urine; the remainder was excreted in feces. 14C Fluphenazine and its enanthate and decanoate esters (1 mg/kg) were administered intravenously to dogs whose bile ducts had been cannulated. The amounts of radioactivity excreted in the urine and bile in 8 hr were very similar, as were the residual amounts of radioactivity present in selected tissues. Comparison of the data obtained from dogs given these three compounds intravenously (unformulated) or intramuscularly in sesame oil points to the following conclusions: (a) fluphenazine base per se does not provide slow-release characteristics unless it has been esterified, for example, with heptanoic or decanoic acid, and (b) intramuscular rather than intravenous administration of these two esters is responsible for producing their slow-release characteristics.

A low-density lipoprotein (LDL):daunomycin complex was prepared which contains, on the average, 8 nmol of daunomycin/mg of apolipoprotein. LDL was not perturbed to any significant degree by association with daunomycin, and the complex remained stable at 4 degrees. Fluorescence quenching with DNA and potassium iodide, antibody precipitation, and density flotation studies suggested at least two domains for localization of the daunomycin, the surface region and the hydrophobic core of the LDL particle. Interaction of the LDL:daunomycin complex with P388 leukemic cells which were sensitive or resistant to daunomycin occurred rapidly in both sublines, with quantitatively larger amounts of the drug being cell associated than when free drug was used alone. The cells appeared morphologically intact, with no nuclear damage after short-term incubation with LDL:daunomycin. Subfractionation of cell membranes and organelles from the sensitive and resistant cell lines incubated with LDL:daunomycin showed accumulation of drug in the plasma membrane and microsomal-lysosomal-mitochondrial membranes and an insoluble nuclear chromatin material. Both 125l-labeled apoprotein and daunomycin from a 125l-LDL:daunomycin complex showed enrichment in similar membrane:organelle fractions of the P388 cells.

8-(Methylthio-14C or -35S)cyclic 3',5'-adenosine monophosphate (I) was given intravenously to rats (5 mg/kg) and orally and intravenously to dogs (0.25, 2.5, or 50 mg/kg). Oral doses were absorbed well but slowly. Plasma half-lives in dogs were about 3 hr after oral or intravenous doses of 0.25 or 2.5 mg/kg and ranged from 5 to 12 hr after oral or intravenous doseas of 50 mg/kg. Plasma glucose and insulin concentrations in dogs were increased by oral or intravenous doses of the compound. Regardless of the route, excretion of radioactivity by rats and dogs at all doses was chiefly in the urine (74-87% of the dose); the remainder was excreted in the feces or bile. Compound I was rapidly distributed to most tissues of dogs but entered the brain and certain portions of the eye slowly and to a limited extent. Urine and plasma of dogs and urine of rats contained I, 8-(methylthio)adenosine, and at least two other unidentified metabolites. Compound I and cyclic 3',5'-adenosine monophosphate were metabolized in vitro by the soluble fraction of dog liver to form 8-(methylthio)adenosine-5'-monophosphate and adenosine-5'-monophosphate, respectively. These compounds were further converted to 8-(methylthio)adenosine and adenosine, respectively. Compound I was metabolized in vitro more slowly than cyclic 3',5'-adenosine monophosphate.

The absorption of captopril (I), a new antihypertensive agent, was studied in mice and rats at doses (50 and 1350 mg/kg) administered in the diet in chronic toxicological studies. 3H- or 35S-Labeled I was administered by gavage and in the diet to male and female animals in a two-way crossover study. Animals received daily doses of nonradiolabeled I in the diet for 25 days, except on Days 15 and 22 when radiolabeled I was administered either by gavage or in the diet. Absorption of the total radioactivity in 2-month-old mice averaged 49 and 48%, respectively, of the 50- and 1350-mg/kg doses given in the diet and 57 and 65%, respectively, of the doses given by gavage. The bioavailability of I in 2-month-old mice averaged 48 and 39% (diet) and 44 and 59% (gavage) of the 50- and 1350-mg/kg doses, respectively. In 2-month-old rats, absorption of the total radioactivity averaged 41% of the 50-mg/kg dose given in the diet. In 2- and 15-month-old rats, minimum absorption of the 1350-mg/kg dose averaged 36 and 45% (diet) and 51 and 71% (gavage), respectively; the minimum bioavailability averaged 20 and 29% (diet) and 39 and 44% (gavage), respectively. These studies demonstrate adequate absorption and bioavailability of I over a wide range of doses from the drug-diet mixtures and by young and old animals and also illustrate a useful experimental design for the estimation of relative oral absorption of a drug administered continuously in the diet over several days.

14C-Captopril was administered as 100-mg tablets to 12 subjects in a two-way crossover study in which subjects were either fasted or were given a standard meal immediately prior to dosing. Based on blood level and urinary excretion data, both the absorption of total radioactivity and the bioavailability of captopril were decreased approximately 35 to 40 per cent after a meal. Whether this moderate decrease in the absorption and the bioavailability of captopril caused by food is of clinical significance has not yet been determined.

We have investigated the in vitro drug-cell interaction and therapeutic effects of a low-density lipoprotein (LDL)-daunomycin complex as compared to free daunomycin. Uptake and retention of daunomycin were significantly enhanced in sensitive and resistant P388 leukemia cells when they were perfused with LDL-daunomycin complex relative to free drug. The interaction of the LDL-daunomycin complex with P388 cells appeared to be through a LDL-specific pathway since competition with free LDL but not high-density lipoprotein significantly reduced daunomycin uptake. The LDL-daunomycin complex was cytotoxic to both daunomycin-sensitive and daunomycin-resistant P388 sublines. Colony growth studies showed the LDL-daunomycin complex to be more cytotoxic at shorter exposure times relative to free drug. Resistant cells showed 55 and 12% colony growth with 10-min and 2-hr exposures, respectively, to 0.4 microgram daunomycin/ml of the LDL-daunomycin complex. Free drug at 0.4 microgram/ml drug concentration and similar exposure times resulted in no loss in colony growth. The resistant cells were subjected to cell cycle analysis based on DNA content and showed an accumulation of cells at the G2-M phase of the cell cycle when treated with the LDL-daunomycin complex, with no effects being observed with free daunomycin.

Single lamellar phosphatidyl[methyl-2H]choline vesicles were incubated with an excess of unlabeled phosphatidylcholine vesicles or phosphatidylcholine-cholesterol vesicles containing 8 mol % glucuronosyldiglyceride. Incubation of the two vesicle populations was performed in the presence or absence of a purified phosphatidylcholine exchange protein. The negatively charged glycolipid donor vesicles could be completely removed by column chromatography on DEAE-Sephacel. Following incubation with exchange protein and subsequent fractionation, the -N(CD3)3 phosphatidylcholine acceptor vesicles exhibited a 61-73% enrichment of the unlabeled phosphatidylcholine in the outer monolayer. Upon incubation in an air atmosphere, no appreciable transbilayer movement of the outer monolayer -N(CH3)3 phosphatidylcholine was observed for at least 5 days. Between days 5 and 7, however, extensive transbilayer movement occurred, leading to an outer monolayer/inner monolayer phosphatidylcholine ratio of 2.1 on day 7. In phosphatidylcholine-6 mol % cholesterol vesicles treated similarly, the outside/inside ratio of the unlabeled phospholipid was 6.7, suggesting a much smaller percentage of transbilayer movement. The loss of transbilayer asymmetry which occurred during a 36-h period after day 5 could be estimated at the upper limit, t 1/2 approximately 7.3 h for phosphatidylcholine vesicles and t 1/2 approximately 53 h for phosphatidylcholine-cholesterol vesicles. The actual rates for transbilayer movement, however, were likely more rapid. Transbilayer movement occurred at a time period when oxidized phospholipid breakdown products had reached critical levels.

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A soluble red band fraction was obtained from Leishmania tarentolae cells by sucrose gradient sedimentation of a Triton X-100 lysate. Spectral analysis indicated that cytochrome b was present in the red band: the reduced minus oxidized difference spectra revealed absorption maxima at 562,527, and 431 nm at room temperature and 562, 530, and 422 nm at 77K. In addition, a 28-kDa protein was identified in this fraction which retained heme-associated peroxidase activity even after denaturation on SDS-polyacrylamide gels. The amino acid composition of this protein showed a strong similarity to cytochrome c1 of both bovine and yeast.

Two-cell mouse embryos were frozen by direct plunging into liquid nitrogen after a 3-min exposure to solutions containing 0.25 M sucrose with 1.5, 3, or 4.5 M dimethyl sulfoxide (Me2SO), and 0, 4, 8, 16, or 32 mg/ml bovine serum albumin (BSA). In the absence of BSA, significantly more embryos were lost or damaged during freezing and thawing. Increasing the BSA concentration from 4 to 32 mg/ml had no significant effect on subsequent embryo viability in vivo or in vitro. Blastocyst formation in vitro was greater than 90% in embryos exposed to the cryoprotective solutions only. Although development to blastocysts was not significantly different to nonfrozen controls in most groups frozen in 3 and 4.5 M Me2SO (up to 92% blastocysts), it was significantly reduced when embryos were frozen in 1.5 M Me2SO (up to 65% blastocysts). The development to fetuses of embryos frozen in 3 M Me2SO (64 to 74% fetuses) was not significantly different from nonfrozen controls (68 to 79% fetuses) or embryos frozen by a conventional slow cooling method (70%). Frozen thawed two-cell embryos developed into normal adults which were able to reproduce normally. We conclude that this freezing method can efficiently cryopreserve early cleavage stage mouse embryos.

8-(Methylthiocyclic AMP-35S was applied topically to the intact or abraded skin of dogs at a dose of about 2-5 mg/kg. In this species, an average of 7% of the dose was absorbed through the intact and 62% through abraded skin. Half-lives for radioactivity in plasma averaged 3-6 h. After the topical application of the drug to the intact skin of dogs, the average concentration in plasma of glucose, but not of insulin, was increased by as much as 21%; after application to abraded skin, glucose and insulin were increased, on average, by as much as 84 and 221%, respectively. 8-(methylthio)adenosine and two unidentified compounds were present as metabolites in the urine of dogs; some unchanged 8-(methylthio)cyclic AMP-35S was also excreted. 8-(methylthio)cyclic AMP-35S was also applied topically (25 mg; 0-32 mg/kg) to the intact and stripped skin of normal human subjects under conditions similar to those used for dogs. Three subjects with intact skin did not absorb any of the drug, whereas three subjects with stripped skin absorbed 0-5, 8-3, and 23-3% of the dose. The half-life of radioactivity in the plasma of the subject with the greatest absorption was 0-5 h during the first 2 h, and 11 h for the next 10 h. During the first 2 h, this same subject excreted unchanged drug and 8-(methylthio)adenosine in his urine. No changes in glucose or insulin concentrations in plasma were observed in any of the subjects nor was there any apparent irritation of the skin.