Postanesthetic theophylline elimination.
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Anesthesia↗
Biomedical subjects
K Nakatsu
Publications and source records attributed to K Nakatsu.
Biotransformation of glyceryl trinitrate occurs concurrently with relaxation of rabbit aorta.
This study was conducted to test the hypothesis that biotransformation of glyceryl trinitrate (GTN) is involved in GTN-induced relaxation of vascular smooth muscle. Isolated rabbit aortic strips (RAS) were contracted submaximally with phenylephrine (PE) and then were incubated with 0.5 microM [14C]GTN in a time course study. GTN-induced relaxation (inhibition of PE-induced tone) of RAS was monitored and tissue GTN and glyceryl-1,2- and 1,3-dinitrate (GDN) concentrations were measured by thin-layer chromatography and liquid scintillation spectrometry at 0.5, 1, 2 and 20 min after incubation. Biotransformation of GTN to GDN occurred during GTN-induced relaxation of RAS. The tissue GDN concentration was dependent on the time duration of incubation with GTN and was related to the magnitude of GTN-induced tissue relaxation. At the 20-min interval, the GDN concentration in the incubation medium indicated appreciable efflux of GDN metabolites from the RAS. In the biotransformation of GTN by RAS, there was about 4-fold preferential formation of 1,2-GDN compared with 1,3-GDN. RAS were made tolerant to GTN in vitro by incubation with 500 microM GTN for 1 hr. After washing, GTN-tolerant and nontolerant (incubation with vehicle for 1 hr) RAS were contracted submaximally with PE, and then were incubated with 0.5 microM [14C]GTN for 2 min. GTN-induced relaxation of RAS and tissue GDN concentration were significantly less for GTN-tolerant tissue compared with nontolerant tissue. Tissue GTN concentration was similar for both GTN-tolerant and nontolerant RAS, which indicated that the tissue uptake of GTN was similar and that GTN biotransformation was diminished in tolerant tissue.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Requirement for reduced, unliganded hemoprotein for the hemoglobin- and myoglobin-mediated biotransformation of glyceryl trinitrate.
The biotransformation of glyceryl trinitrate (GTN) by hemoglobin (Hb) and myoglobin (Mb) was assessed using solutions of various forms of the hemoproteins, viz., the oxy-, deoxy-, carbonmonoxy- and met-forms. After incubation with these, GTN loss was observed only with the deoxy-forms of Hb and Mb. The stoichiometry and products of [14C]GTN biotransformation by deoxy-Hb and deoxy-Mb were determined by measuring the formation of [14C]glyceryl dinitrate [14C]GDN), met-Hb (or met-Mb) and inorganic nitrite anion. Biotransformation of GTN involved the oxidation of 2 mol of heme iron (II) per mol of GTN biotransformed to GDN and inorganic nitrite anion. In addition to the formation of GDN, 1 to 2.5% of the radioactivity could not be extracted from the incubation samples. The ratio of 1,2-GDN/1,3-GDN formed during incubation of deoxy-Hb with GTN was 11:1, which indicated a high degree of regioselectivity for the denitration of the nitrate ester group in position 1 or position 3 of GTN. The metabolite ratio obtained for deoxy-Mb incubation with GTN (1,2-GDN/1,3-GDN,3:1) was less than that for deoxy-Hb, which indicated less regioselectivity for the deoxy-Mb-mediated denitration reaction. This could reflect differences in the topography of the heme pocket of the two hemoproteins and steric differences in the GTN-hemoprotein interaction.
Biotransformation↗
Limitation of theophylline elimination by reduced oxygen availability in mouse hepatocytes and rat isolated livers.
The effect of oxygen availability on theophylline metabolism by mouse hepatocytes and rat isolated livers was examined. The elimination of theophylline by mouse hepatocytes and the metabolism of theophylline to dimethyluric acid by isolated, perfused rat livers was seriously impaired when the gas mixture supplied contained less than 28% oxygen. The correlation coefficients relating oxygen supply and the concentration of theophylline remaining in mouse hepatocyte suspensions were -0.74 to -0.84. In the isolated, perfused rat liver experiments, the correlation coefficient relating oxygen availability and dimethyluric acid production was 0.87. These observations are interpreted as supporting the hypothesis that oxygen availability per se is an important factor in determining the rate of theophylline metabolism.
Aerobiosis↗
Mycinamicins, new macrolide antibiotics. VIII. Chemical degradation and absolute configuration of mycinamicins.
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Anti-Bacterial Agents↗
Role of hemoglobin in the differential biotransformation of glyceryl trinitrate and isosorbide dinitrate by human erythrocytes.
Incubation of 2 X 10(-7) M glyceryl trinitrate (GTN) at 37 degrees C with human red blood cells resuspended in saline resulted in a 73.4 +/- 3.5% (S.D.) elimination of GTN after 10 min. The elimination of GTN was accompanied by the appearance of an equimolar amount of the GTN metabolites. The biotransformation of GTN and another organic nitrate, isosorbide dinitrate (ISDN), was examined in more detail using the 25,000 X g supernatant fraction of human red blood cells (RBC-SF). Incubation of 2 X 10(-7) M GTN or ISDN at 37 degrees C with RBC-SF resulted in a 46.3 +/- 7.3% (S.D.) elimination of GTN after 40 min and a 51.8 +/- 5.9% (S.D.) elimination of ISDN after 240 min. The elimination of the parent organic nitrate was accompanied by the appearance of an equimolar amount of metabolites. The biotransformation of ISDN was inhibited completely by pretreatment of the RBC-SF with trypsin, N-ethylmaleimide or heating at 65 degrees C, whereas GTN biotransformation was only inhibited partially by these treatments. Biotransformation of GTN was inhibited partially by pretreatment of the RBC-SF with CO or potassium ferricyanide; these treatments had no effect on ISDN biotransformation. Treatment of the RBC-SF with the combination of N-ethylmaleimide plus CO or trypsin plus CO resulted in complete inhibition of GTN biotransformation. We conclude that ISDN biotransformation by erythrocytes is a sulfhydryl-dependent enzymatic process, whereas the biotransformation of GTN is due to a combination of a sulfhydryl-dependent enzymatic process and an interaction with reduced hemoglobin.
Adult↗
Suicidal destruction of cytochrome P-450 and reduction of ferrochelatase activity by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine and its analogues in chick embryo liver cells.
The ferrochelatase-reducing activity and cytochrome P-450- and heme-destructive effects of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were studied in chick embryo liver cells. A group of DDC analogues was found in which an inability to reduce ferrochelatase activity corresponded with an inability to cause cytochrome P-450 and heme destruction. In a second group of DDC analogues, the ability to reduce ferrochelatase activity corresponded with the ability to cause cytochrome P-450 and heme destruction. These observations support the idea that the protoporphyrin IX moiety of N-alkylprotoporphyrin IX originates from the heme moiety of cytochrome P-450. A third group of DDC analogues caused cytochrome P-450 and heme destruction despite an inability to reduce ferrochelatase activity. With this third group of DDC analogues, the heme moiety of cytochrome P-450 is likely degraded to products other than N-alkylporphyrins. The inability of several lipophilic DDC analogues [4-benzyl, 4-isopropyl, 4-cyclohexyl, 4-(3-cyclohexenyl)] to reduce hepatic ferrochelatase activity may explain their low porphyrinogenicity. The pattern of porphyrin accumulation produced in response to two DDC analogues that did not inhibit ferrochelatase was investigated using high performance liquid chromatography. Coproporphyrin was the major porphyrin to accumulate in response to the 4-isopropyl analogue and uro- and heptacarboxylic acid porphyrins in response to the 4-benzyl analogue. These patterns of porphyrin accumulation are consistent with the inability of these analogues to inhibit ferrochelatase.
Animals↗
Anesthetics and theophylline metabolism.
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Animals↗
Evaluation of 3,6-dibutanoylmorphine as an analgesic in vivo: comparison with morphine and 3,6-diacetylmorphine.
Dibutanoylmorphine (DBM), a synthetic diester of morphine, was compared with morphine (M) and diacetylmorphine (DAM) for analgesic efficacy, potency and duration of action following I.V. administration in rats. Analgesia was assessed in groups of eight animals using both tail-flick and hot-plate testing methods following random administration of five different doses of each drug. DBM was found to be substantially more potent than M, but less potent than DAM in both tail-Flick and hot-plate tests of nociception. Similarly, assessment of duration of action at the ED50 for each drug revealed that DBM has a duration of analgesia which is intermediate between the durations of M and DAM. Thus, in rats in vivo, DBM is an effective analgesic and has a reasonable duration of action release to other opioids.
Analgesics↗
A simple, less stressful rat restrainer.
The construction of a simple, inexpensive animal restrainer is described. Data are given showing its utility in analgesia studies.
Analgesia↗
Relative cataleptic potency of narcotic analgesics, including 3,6-dibutanoylmorphine and 6-monoacetylmorphine.
Dose-response curves were constructed for duration of significant catalepsy in male Sprague-Dawley rats following i.p. administration of four established and two novel narcotic analgesics. The relative potency of the six drugs was levorphanol greater than monacetylmorphine greater than diacetylmorphine greater than dibutanoylmorphine greater than morphine greater than meperidine. Cataleptic potency correlated with analgesic potency for morphine, diacetylmorphine, and dibutanoylmorphine but not for monoacetylmorphine.
Animals↗
Morphine diesters. I. Synthesis and action on guinea pig ileum.
3,6-Dipropanoylmorphine (DPM), 3,6-dibutanoylmorphine (DBM), and 3,6-dihexanoylmorphine (DHM) were prepared as prospective long-acting narcotic analgesics. The purity and structure of these compounds were authenticated by high pressure liquid chromatography and direct probe mass spectrometry. In aqueous solution the stability of the HCI salts of these compounds decreased with increasing alkyl chain length such that DHM underwent rapid hydrolysis to 6-monohexanoylmorphine (MHM). A comparison of DPM, DBM, and MHM with morphine (MO) and 3,6-diacetylmorphine (DAM, heroin) in the electrically stimulated guinea pig ileum myenteric plexus longitudinal muscle strip preparation (GUPIL) revealed similar potencies and efficacies for all compounds, but marked differences in the onset of drug action (MO greater than DAM greater than MHM greater than DPM greater than DBM, faster to slower). In a periodically washed GUPIL preparation DBM and MHM were five times longer acting than MO, DAM or DPM.
Animals↗
Morphine diesters. II. Blood metabolism and analgesic activity in the rat.
The kinetics of hydrolysis of dipropanoylmorphine (DPM) and dibutanoylmorphine (DBM) in human blood fractions and for diacetylmorphine (DAM) and DBM in rat blood fractions were investigated. In each case the hydrolysis of morphine diesters terminated with the production of the corresponding 6-monoester derivative. Generally, decreases in Km and Vmax were observed for the plasma, red blood cell (RBC) cytosol, and RBC membrane esterases responsible for morphine diester hydrolysis as the alkyl chain length of the ester moiety increased. This resulted in an overall decrease in the rate of hydrolysis of morphine diesters by human or rat blood with longer chain homologs of DAM. The analgesic potency and duration of morphine, DAM, and DBM were assessed at various i.v. dosages in the rat by means of the tail-flick latency test. A comparison of equianalgesic doses of morphine, DAM, and DBM indicated that DAM and DBM were 11.5 and 6 times as potent and 0.8 and 1.2 times as long acting, respectively, as morphine.
Analgesics↗
Biotransformation of glyceryl trinitrate to glyceryl dinitrate by human hemoglobin.
The elimination of glyceryl trinitrate (GTN) by man is rapid and its clearance exceeds cardiac output. It is therefore clear that a variety of tissues in addition to liver are involved in the biotransformation of GTN. Incubation of GTN with the 25 000 X g supernatant fraction of lysed human erythrocytes resulted in a 39.6% +/- 5.5 (SD) elimination of GTN after 40 min. After pretreatment of the lysate supernatant fraction with carbon monoxide, GTN elimination was only 26% +/- 4.5. These data indicated that hemoglobin might be involved in GTN elimination. When purified hemoglobin was incubated with GTN, a 77.1% +/- 6.4 elimination of GTN was observed, accompanied by glyceryl dinitrate formation. The biotransformation of GTN was inhibited by pretreatment with carbon monoxide. The results indicate that the biotransformation of GTN by human erythrocytes is due, at least in part, to interaction with hemoglobin.
Adult↗
Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings.
The ability of isosorbide dinitrate (ISDN) and its two metabolites, 5-isosorbide mononitrate (5-ISMN) and 2-isosorbide mononitrate (2-ISMN), to relax phenylephrine-contracted rabbit aortic rings was compared. The three organic nitrates demonstrated similar efficacy. ISDN was found to be the most potent (median effective dose (ED50); 1.5 X 10(-7) +/- 1.1 X 10(-7) M), followed by 2-ISMN (ED50, 1.8 X 10(-6) +/- 9 X 10(-7) M) and 5-ISMN (ED50, 8.2 X 10(-6) +/- 3.6 X 10(-6) M). The log dose-response curve of ISDN in rabbit aortic rings was constructed in the absence and presence of three fixed concentrations of 5-ISMN (5 X 10(-6), 10(-5), and 3 X 10(-5) M). No shift in the ISDN dose-response curve at high ISDN concentrations was noted in the presence of 5-ISMN. Using the isobolographic method with fixed ISDN/5-ISMN ratio mixtures, no evidence for an antagonistic effect of 5-ISMN on ISDN-induced vasodilation was obtained. Analysis of the fixed ISDN/5-ISMN ratio mixture responses by the median-effect plot showed no antagonistic effect. It is concluded that in rabbit aortic rings 5-ISMN, the major metabolite of ISDN, is not an antagonist of ISDN at a "nitrate receptor," and no support is provided for the hypothesis that the accumulation in plasma of metabolites (e.g., 5-ISMN) with longer half-lives than the parent drug explains tolerance to organic nitrates.
Animals↗
The disposition and the liver and thymus gland toxicity of 3,3',4,4'-tetrachlorobiphenyl in the female rat.
3,3',4,4'-Tetrachlorobiphenyl (TCBP) was administered orally to adult female Sprague--Dawley rats in the oral dosage regimen, 5 mg X kg-1 X day-1 for 21 days, followed by a 22-day postdosing period. Control animals received either the corn-oil vehicle (1 mL X kg-1 X day-1) or no treatment. 3,3',4,4'-TCBP distributed preferentially into the adipose tissue and liver, and apparent steady-state xenobiotic concentrations were attained in the adipose tissue (8 micrograms/g) and liver (300 ng/g) prior to the cessation of dosing. The 3,3',4,4'-TCBP concentrations in the serum, brain, kidneys, and thymus gland were lower and more variable than those in the adipose tissue and liver. During the postdosing period, 3,3',4,4'-TCBP was eliminated from the adipose tissue and liver by apparent first-order kinetics with elimination half-life values of 2.5 days and 0.8 day, respectively. The major route of excretion of unmetabolized 3,3',4,4'-TCBP was via the feces, and the amount excreted over 24 h did not exceed 8% of the dose administered on any given day. Throughout the experiment, there were no differences in the body weight or food and water intake for the 3,3',4,4'-TCBP-treated animals compared with the corn-oil-treated and nontreated rats. There was a significant increase in liver weight and a significant decrease in thymus gland weight for the 3,3',4,4'-TCBP-treated rats compared with the corn-oil-treated rats at the cessation of dosing and at 11 days thereafter, but there were no observable histological changes in these organs as assessed by light microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Theophylline clearance. Lack of effect of influenza vaccination and ascorbic acid.
Warnings have been issued regarding safety in the use of theophylline preparations in patients receiving influenza vaccination. These were prompted by reports that influenza vaccination caused inhibition of metabolism of theophylline and aminopyrine. Previous work has indicated a role for ascorbic acid in mixed function oxidase activity, and ascorbic acid is commonly used by the public. We studied the effect of influenza vaccination and ascorbic acid supplementation on the rate of elimination of theophylline. In 11 patients and 12 normal subjects no significant effects of influenza vaccination or ascorbic acid supplementation on theophylline clearance, serum half-life, or apparent volume of distribution were detected (p greater than 0.3). We conclude that neither influenza vaccination nor ascorbic acid supplementation induce a predictable effect on theophylline disposition.
Adult↗
Theophylline reassessed.
Advances have recently been made in understanding the pharmacokinetics of theophylline. To correlate the new knowledge of theophylline pharmacokinetics with the drug's current status in therapy, we have critically reviewed the relevant investigations of the last 5 years. We consider data on its presumed mechanisms of action, factors affecting its clearance, its use in pregnancy, treatment of overdoses, and important drug interactions. Theophylline clearance is decreased by concomitant use of erythromycin, cimetidine, high-dose allopurinol, oral contraceptives, and caffeine. Clearance is increased by concomitant use of phenobarbital and phenytoin. Newly discovered actions of theophylline include dose-dependent improvement of diaphragmatic contractility, augmentation of ventilatory response to hypoxia, and sleep disturbances (especially with high-dose treatments). Points clinically relevant to the daily use of theophylline derivatives and the importance of sustained-release preparations are discussed. Theophylline continues to play a major role in therapy for reactive airways disease.
Acidosis↗