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H M Mehendale

Publications and source records attributed to H M Mehendale.

207 records · Page 12Linked to original sources
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Absence of metabolism of morphine during accumulation by isolated perfused rabbit lung.

Pulmonary accumulation and metabolism of morphine was studied in an isolated perfused lung system. No metabolism of morphine or N-demethylation of ethylmorphine was found. Accumulation from the recirculating perfusate was nonsaturable over a concentration range of 3-400 microM morphine. Inhibition of sodium transport or sodium depletion decreased morphine accumulation. The results are most consistent with passive diffusion of morphine down an electrochemical gradient and subsequent nonspecific binding to tissue anions. Normal movement of sodium and potassium is required to maintain this gradient.

Animals↗
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Uptake and disposition of chlorinated biphenyls by isolated perfused rat liver.

The hepatic disposition of four chlorinated biphenyls was studied in isolated perfused rat liver preparations perfused with 30% rat blood. Biliary excretion of 14C-labeled 4-chlorobiphenyl (1-CB): 4,4'-dichlorobiphenyl (2-CB): 2,4,5,2',5'-pentachlorobiphenyl (5-CB) and 2,4,5,2',5'-hexachlorobiphenyl (6-CB) appeared to be inversely related to increased chlorination. Each of the compounds was rapidly taken up by the liver from the circulating perfusate. After 4 hr of perfusion, biliary excretion of 14C from 1-CB, 2-CB, 5-CB, and 6-CB was 48.2, 29.6, 20.5, and 1.3% of total dose, respectively. For 1-CB, this rate of biliary elimination represents a maximum perfusate/bile ratio of 107. About 97% of the label in the bile from 1-CB experiments was in the form of metabolites. Biliary excretion of 1-CB was biphasic: an initial rapid phase (t 1/2 = 13 min) was followed by a slower second phase (t 1/2 = 122 min). When the metabolites of 1-CB were added to the perfusate, biliary excretion of these metabolites was monophasic; t 1/2 = 120 min, which corresponded to the slower phase observed when the parent compound was presented to the liver. 1-CB disappeared from the perfusate via a biphasic process. Metabolites of 1-CB effused into the perfusate immediately after the initial rapid uptake of 1-CB by the liver, and the recirculating pool of metabolites was eliminated in the bile by the slow postsynthetic phase of biliary elimination. Less than 2% of 1-CB was present as the parent compound in the perfusion system after 4 hr of perfusion. These findings indicate that the metabolism of 1-CB is not the limiting factor in the hepatic disposition of 1-CB and that the circulating metabolites of 1-CB effusing from the liver might be the major source for urinary excretion.

Animals↗
PubMedDate not supplied

Uptake and metabolism of chlorpromazine by rat and rabbit lungs.

Isolated perfused rat lung and in vitro rat and rabbit lung preparations were used to study the pulmonary uptake and metabolism of chlorpromazine (CPZ). Rat lungs were artificially ventilated and perfused via pulmonary artery with recirculating perfusate containing 1.7--180 microM 14C-CPZ. In the perfusate, 14C-CPZ-derived radioactivity declined rapidly, representing maximal pulmonary uptake at 5 min. Thereafter, the total radioactivity in the perfusate increased steadily. During the latter phase, the appearance of CPZ metabolites in the perfusate more than offset the continued decline in CPZ, suggesting metabolism of previously sequestered CPZ and a net, steady efflux of metabolites from the lung. Increasing concentration of metabolites paralleled the increase in total 14C in the perfusate. The principal metabolite was identified as CPZ-N-oxide. Biotransformation of CPZ by the perfused rat lung was temperature-sensitive and dependent on substrate concentration. Substrate saturation was apparent at 120 microM CPZ in the perfusate. In vitro incubation of 14C-CPZ with 9000g supernatant fractions of rat and rabbit lungs revealed that CPZ-metabolizing activity of rat lungs is far greater than that of rabbit lungs. In accordance with the perfusion studies, the principal pathway was N-oxidation of CPZ in the rat lung incubations. Although quantitatively much less significant, CPZ was metabolized in rabbit lung incubations, via demethylation. SKF 525-A did not inhibit CPZ metabolism by perfused or in vitro rat lung preparations, but selectively enhanced N-oxidation of CPZ. Piperonyl butoxide was without any effect. Metabolism of CPZ by rabbit lung incubations was inhibited by SKF 525-A and piperonyl butoxide. These results suggest that CPZ is metabolized by the rat lungs principally via N-oxidation by a pathway not involving cytochrome P-450; the resultant metabolite, CPZ-NO, is released into the circulation, indicating significantly lower affinity for the lung tissue than the parent compounds.

Animals↗
PubMedDate not supplied

Effect of chlorphentermine pretreatment on chlorphentermine uptake by isolated perfused rat lung.

Chlorphentermine (CP), an anorectic agent currently in use, is known to be highly accumulated in the lung, causes pulmonary phospholipidosis, and has been suspected of causing pulmonary hypertension. These studies were undertaken to characterize the uptake and accumulation processes and to examine the effect of subacute CP treatment on the uptake kinetics of CP in the rat lung. Animals were treated po with a saline solution of CP (50 mg/kg/day) for 7 days and the controls received the vehicle only. Artificially ventilated isolated rat lung preparations were perfused with Krebs-Ringer bicarbonate buffer containing bovine serum albumin. CP was not metabolized by control or pretreated perfused lungs or by their 9000g supernatant or microsomal fractions. In recirculating perfusion experiments, steady-state uptake was reached after 20 min of perfusion with 0.17 mM CP. Lungs from rats treated with CP as described above accumulated CP to a greater extent and more rapidly than did lungs from control rats. Similarly, lungs from rats treated with CP accumulated significantly greater quantities of CP than control lungs during single-pass perfusion experiments. Whereas control lungs reached a steady state uptake within 7 min, lungs from CP treated animals failed to reach a steady-state uptake during a 10-min perfusion. The lungs from CP-treated rats retained most of the accumulated CP and exhibited a significantly increased half life of efflux in comparison to control rats. Removal of Na+ from the perfusion medium or the addition of harmaline significantly decreased the half-life of CP uptake and the amount of CP accumulated by the lung.

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