Biomedical subjects
Publications and source records attributed to T C Orton.
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We have investigated the dynamics for the removal of 5-hydroxytryptamine (5-HT) from the circulation using the isolated perfused rabbit lung. 5-HT was removed from the circulation at a constant rate and metabolized completely to 5-hydroxyindoleacetic acid which effluxed from the lung into the circulation. Two methods were developed to determine the constant rate of removal of 5-HT: (1) the constant rate is equal to the difference between the 5-HT concentration flowing into the lung and the 5-HT concentration in the effluent times the flow rate and (2) extrapolation of the rate of appearance of radioactivity in the effluent to zero time. With these methods, we have confirmed the 5-HT is removed by the lung by a carrier-mediated Na+-dependent transport system. Studies of transport systems in perfused organs required an adequate supply of the chemical to the lung. Supply rates less than removal rate will result in erroneous measurements of the constant removal rate. The relationships between the rate of removal, perfusate concentration and perfusion rate were analyzed.
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1. (14)C-Methsuximide (N-methyl-(14)C-2-methyl-2-phenylsuccinimide) was rapidly absorbed from the small intestine of the rat (t(1/2) 17.4 min).2. The drug was rapidly and fairly evenly distributed throughout the body with peak blood and tissue levels occurring 1 h after oral administration. At all times, adrenals, body fat, kidneys and liver had higher levels of (14)C-methsuximide than other tissues and the drug freely traversed the blood-brain barrier. However, radioactivity disappeared rapidly from most tissues after the initial phase of the distribution.3. During 24 h, 26% of the orally administered radioactivity was recovered in urine and 29% appeared in expired air as (14)CO(2). The excretion of (14)CO(2) indicated N-demethylation of (14)C-methsuximide to 2-methyl-2-phenylsuccinimide. 2.7% of an administered dose of methsuximide was excreted unchanged in 24 h urine and 2.7% appeared as 2-methyl-2-phenylsuccinimide. 2-Methyl-2-phenylsuccinimide was also detected as a urinary metabolite of methsuximide in man.4. 2-Methyl-2-phenylsuccinimide possesses anticonvulsant activity and it is suggested that this metabolite contributes to the overall anticonvulsant activity and toxicity of methsuximide.5. Rat urine also contained a radioactive substance with similar chromatographic properties to one of the products of alkaline hydrolysis of methsuximide. This compound may arise from the spontaneous decomposition of the parent drug in vivo.
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Rapid and accurate prediction of teratogenic hazard had been achieved using cultures of differentiating limb mesenchyme (LB) and midbrain (CNS) cells from 13-day-old rat embryos. In this study we have used these cultures to examine the role of metabolism in the in vitro teratogenic activity of diphenylhydantoin (DPH) and cyclophosphamide (CPA). Two approaches were used. The first involved modulation of cytochrome P-450 activity by co-incubation in vitro with a variety of inhibitors at concentrations that were non-cytotoxic to the cells. This enhanced the toxicity of DPH by 13-82% in LB and by 3-52% in CNS cells. Benzimidazole and ellipticine caused the greatest enhancement and SKF 525A the least. DPH appears to be the proximate teratogen and there appear to be embryo-tissue cytochrome P-450s that assist in its detoxification. Following prior transplacental induction, CPA was toxic in vitro to LB cells from beta-naphthoflavone-pretreated mothers. CPA was non-toxic in cells of control, phenobarbitone- or 3-methylcholanthrene-treated embryos. Thus there appear to be inducible levels of cytochrome P-448 in embryo cells. In the second approach, positive immunocytochemical staining of the cells with both monoclonal and polyclonal P-450 antibodies identified phenobarbitone, beta-naphthoflavone- and 3-methylcholanthrene-inducible cytochrome P-450s at a constitutive level. Cytochromes P-448 (beta-naphthoflavone type) and P-450 (phenobarbitone type, PB3 fraction) were inducible, confirming that cytochrome P-450s are in fact present in the embryo cells.
An isolated perfused rabbit lung preparation (IPL) was used to study the uptake, accumulation, and efflux of the tricyclic amine imipramine (IMIP). The rate of IMIP uptake into the IPL was resolved into two exponential components (rates 1 and 2 of uptake). The initial velocities for these uptake components were linearly related to the concentration of IMIP in the perfusate (Cp). This linear relationship indicates that IMIP accumulated in the IPL by diffusion and/or binding. The steady-state accumulation of IMIP was obtained by integration of the exponential expression relating the rate of IMIP uptake to time. The amount of IMIP accumulated at steady state by rate 1 was linearly related to Cp, whereas the amount of IMIP accumulated at steady state by rate 2 was saturable with respect to Cp. These steady-state data are in agreement with the steady-state accumulation data previously reported from experiments with the recirculating blood-perfused rabbit lung. In the absence of IMIP in the perfusate. IMIP that had previously accumulated in the IPL effluxed from the lung at three rates (t1/2 = 18 sec, 58 sec, and 8.25 min), which indicates that accumulated IMIP was in at least three pools in the lung. In addition, a noneffluxable pool was detected which was not the result of irreversible binding to tissue.ated in pools 1 and 2 by rate 1 of uptake. The IMIP in pool 3 and in the noneffluxable pool was accumulated in the IPL by rate 2 of uptake. Efflux pool 3 and the IMIP accumulated at a steady state by rate 2 of uptake were resolved by a Hofstee plot into a biphasic curve indicating two types of binding sites. The noneffluxable pool of IMIP in the IPL was saturable with increasing Cp and represented approximately 30% of the IMIP accumulated by rate 2 into pool 3. Rate 2 of uptake, pool 3, and particularly the noneffluxable pool of IMIP in the IPL are possibly responsible for the accumulation and persistence of Imip in the lung as seen in whole body distribution studies. The physicochemical properties of IMIP and other compounds known to be accumulated in lung tissue are discussed in relation to the possible involvement of lung phospholipids and the compartmentalization of IMIP in the concentric lamellar organelles of the lung.
The effect of chronic dietary administration of the hypolipidemic agents, clofibrate, methylclofenapate, fenofibrate, and tibric acid, on the hepatic drug-metabolizing enzyme system of the albino rat has been studied. Each compound caused dose-dependent increase in liver size and cytochrome P-450 (methylclofenapate = fenofibrate = tibric acid greater than clofibrate). NADPH-cytochrome c reductase activity was increased only after clofibrate and methylclofenapate treatment. There was no overall increase in the metabolism of a number of commonly used model substrates in parallel with the cytochrome P-450 induction. Aminopyrine and ethoxyresorufin dealkylation, biphenyl 4-hydroxylation, testosterone 16 alpha-hydroxylation, and o-aminophenol and chloramphenicol glucuronidation showed no change or inhibition, whereas ethoxycoumarin and phenacetin dealkylation and testosterone 6 beta-hydroxylation were increased (only up to 2-fold). Using clofibrate as a representative of this class of pharmacological agent, the enzymatic changes were essentially reversed within 6 days after removal of drug from the diet. Clofibrate administration also increased liver size and, to a lesser extent, hepatic cytochrome P-450 content in the albino (CD-1) mouse but had no effect in the marmoset monkey. In the rat, clofibrate administration specifically increased the hepatic microsomal omega-hydroxylation of lauric acid approximately 28-fold, which contrasted with the specific increase in (omega - 1)-hydroxylation caused by phenobarbital administration. The specific increase in microsomal cytochrome P-450-mediated omega-oxidation of a medium length, straight chain, saturated fatty acid is similar to the documented increase in peroxisomal and mitochondrial fatty acid beta-oxidation caused by administration of hypolipidemic agents.
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