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The pharmacokinetics of tripelennamine (T) was compared in horses (n = 6) and camels (n = 5) following intravenous (i.v.) administration of a dose of 0.5 mg/kg body weight. Furthermore, the metabolism and urinary detection time was studied in camels. The data obtained (median and range in brackets) in camels and horses, respectively, were as follows: the terminal elimination half-lives were 2.39 (1.91-6.54) and 2.08 (1.31-5.65) h, total body clearances were 0.97 (0.82-1.42) and 0.84 (0.64-1.17)L/h/kg. The volumes of distribution at steady state were 2.87 (1.59-6.67) and 1.69 (1.18-3.50) L/kg, the volumes of the central compartment of the two compartment pharmacokinetic model were 1.75 (0.68-2.27) and 1.06 (0.91-2.20) L/kg. There was no significant difference (Mann-Whitney) in any parameter between camels and horses. The extent of protein binding (mean +/- SEM) 73.6 + 8.5 and 83.4 +/- 3.6% for horses and camels, respectively, was not significantly statistically different (t-test). Three metabolites of T were identified in urine samples of camels. The first one resulted from N-depyridination of T, with a molecular ion of m/z 178, and was exclusively eliminated in conjugate form. This metabolite was not detected after 6 h of T administration. The second metabolite, resulted from pyridine ring hydroxylation, had a molecular ion of m/z 271, and was also exclusively eliminated in conjugate form. This metabolite could be detected in urine sample for up to 12 h after T administration. The third metabolite has a suspected molecular ion of m/z 285, was eliminated exclusively in conjugate form and could be detected for up to 24 h following T administration. T itself could be detected for up to 27 h after i.v. administration, with about 90% of eliminated T being in the conjugated form.

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The conversion of tertiary amines to quaternary ammonium glucuronides was investigated in human liver microsomes, and characteristics of the UDP-glucuronosyltransferase (UGT) catalyzing quaternary ammonium glucuronidation were evaluated. In addition, a rabbit liver microsomal UGT mediating this reaction was studied. The kinetics of quaternary ammonium glucuronidation of cyproheptadine, tripelennamine, amitriptyline, and doxepin in intact human liver microsomes was determined. Tripelennamine was found to have the lowest apparent KM and was used as a representative substrate for further studies. A polyclonal antibody preparation raised in sheep against rabbit liver p-nitrophenol UGT was found to inhibit tripelennamine glucuronidation in solubilized human liver microsomes, but had no effect on p-nitrophenol, 4-methylumbelliferone, 4-aminobiphenyl, estriol, morphine, or naloxone glucuronidation. This antibody also inhibited tripelennamine glucuronidation in solubilized rabbit liver microsomes, but had little or no effect on estrone, testosterone, estradiol, androsterone, and morphine glucuronidation. Chlorpromazine competitively inhibited tripelennamine glucuronidation. This inhibition was markedly enhanced by UV light irradiation. [3H] Chlorpromazine binding to solubilized human liver microsomes was also increased by UV light. The binding was antagonized by substrates for tertiary amine UGT but not by substrates for morphine UGT. These studies suggest that the tertiary amine UGT is photo-affinity-labeled by chlorpromazine. Furthermore, it would appear from immunoinhibition and [3H]chlorpromazine labeling experiments that tertiary ammonium glucuronidation is catalyzed by a unique and distinct UGT in rabbit and human liver microsomes.

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Volunteers were injected im with 100 mg of tripelennamine (pyribenzamine).HCl dissolved in saline. Timed urine was collected. Tripelennamine and its metabolites were identified by GC/MS. Amounts of free tripelennamine excreted in the 0-2-, 2-4-, 4-8-, 8-12-, and 12-24-h urine samples were found to be 0.30, 0.56, 0.17, 0.21, and 0.0%, respectively, of the administered dose. In the same time periods, total tripelennamine (free plus conjugated) amounts were found to be 0.92, 1.20, 0.96, 1.30, and 1.31%, respectively, and total amounts 2-[alpha-hydroxybenzyl(2-dimethylaminoethyl)amino]pyridine(alpha- hydroxytripelennamine) plus an unidentified metabolite were found to be 0.16, 3.35, 3.06, 7.46, and 8.85% of the dose, respectively.

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N-(2-Dimethylaminoethyl)benzylamine and 2-benzylaminopyridine were identified as two new urinary metabolites of tripelennamine in the rat by GC/MS. 2-(4-Methoxybenzylamino)-pyridine and N-(dimethylaminoethyl)-4-hydroxybenzylamine were identified as new urinary metabolites of pyrilamine by GC/MS. Thus, in addition to N- and O-demethylation, hydroxylation, and glucuronidation, N-debenzylation, N-depyridination and N-dedimethylaminoethylation were shown to be novel pathways for metabolism of tripelennamine and pyrilamine. The mechanism for N-depyridination and N-dealkylation is discussed.

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1. In vitro metabolism of methaphenilene (MFN) and pyribenzamine (PBZ) was compared to that of methapyriline (MPH) in rat, because chronic treatment with MPH causes cancer in rats, whereas MFN and PBZ cause no cancer. 2. G.l.c. and mass spectrometry were used to identify 7 metabolites of MFN and 6 of PBZ in extracts of rat liver microsome incubations. 3. Quantification of the metabolic pathways revealed that N-oxide formation is considerably more important for both MFN and PBZ than for MPH, and only MPH forms an amide as a metabolic product. 4. Quantitative balance studies show that a lower recovery is apparent for metabolic experiments with MPH than for either MFN or PBZ under all conditions examined, indicating that significant metabolic pathways for MPH exist which are not being measured under these conditions.

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1. Strains of the fungus Cunninghamella elegans ATCC 9245 and 36112 were tested for their ability to transform the antihistamines methapyrilene (I), thenyldiamine (II) and tripelennamine (III). 2. Antihistamine metabolites were isolated by h.p.l.c., and identified by their 1H-n.m.r. and mass spectral properties. 3. All three drugs were transformed by both C. elegans strains to N-oxidized and N-demethylated derivatives. Metabolism during 96 h of incubation amounted to 85% for (I), 64% for (II), and 83% for (III). Metabolites soluble in organic solvents amounted to 62% to 86% of the total metabolism; approximately 88% to 95% of the organic-soluble metabolites were N-oxide derivatives of each antihistamine.

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Male Sprague-Dawley rats received 20 mg/kg of pyrilamine or tripelennamine intraperitoneally. The extract obtained from an enzymatically hydrolyzed urine was derivatized with or without Tri-Sil Z and analyzed by GC/MS. 2-(2-Dimethylaminoethyl)aminopyridine, 2-(4-hydroxybenzyl)aminopyridine, 2-[4-hydroxybenzyl-(2-dimethylaminoethyl)amino]pyridine, 2-[4-hydroxybenzyl-(2-methylaminoethyl)amino]pyridine, 2-[4-hydroxy-3-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine, and 2-[3-hydroxy-4-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine were detected as metabolites of pyrilamine. 2-(2-Dimethylaminoethyl)aminopyridine, 2-(alpha-hydroxybenzyl)aminopyridine, 2-[alpha-hydroxybenzyl-(2-dimethylaminoethyl)amino]pyridine, 2-[4-hydroxybenzyl-(2-dimethylaminoethyl)amino]pyridine, 2-[4-hydroxy-3-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine, and 2-[3-hydroxy-4-methoxybenzyl-(2-dimethylaminoethyl)amino]pyridine were detected as metabolites of tripelennamine. Thus, N-debenzylation of tripelennamine and N-demethoxybenzylation of pyrilamine occurs in vivo, through an intermediate of alpha-carbon oxidation and represents a new metabolic pathway for these compounds. The identity of the metabolite was confirmed by comparison with an authentic sample of 2-(2-dimethylaminoethyl)aminopyridine. The pharmacological implication of 2-(2-dimethylaminoethyl)aminopyridine, one of the metabolites of pyrilamine and tripelennamine, is discussed.

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The pharmacokinetics of single and combined doses of pentazocine HCl (40 and 80 mg) and tripelennamine HCl (50 and 100 mg) were studied in six healthy drug abusers. After intramuscular administration of 40 or 80 mg pentazocine alone, mean peak plasma concentrations at 15 minutes were 102 and 227 ng/ml, respectively, and mean plasma t1/2 values were 4.6 and 5.3 hours, respectively. After intramuscular administration of 50 or 100 mg tripelennamine, mean plasma concentrations at 30 minutes were 105 and 194 ng/ml, respectively, and mean plasma t1/2 values were 2.9 and 4.4 hours, respectively. After concurrent administration of pentazocine with tripelennamine, plasma pentazocine and tripelennamine concentrations at all time points were not significantly different from those when pentazocine or tripelennamine was administered alone. Coadministration of pentazocine and tripelennamine had no effect on the distribution, elimination, and clearance of either pentazocine or tripelennamine. In conclusion, there did not appear to be a clinically significant metabolic interaction between pentazocine and tripelennamine.

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The effect of tripelennamine on pentazocine antinociception in rats was investigated utilizing a low temperature (51.5 degrees C) hot-plate technique. Tripelennamine (10 and 20 mg/kg i.p.) showed some antinociceptive activity, which was not antagonized by naloxone. Pentazocine antinociception was potentiated by simultaneous administration of a large dose (20 mg/kg) but not a small dose (5 mg/kg) of tripelennamine. Potentiation was not observed when tripelennamine was administered 2 hr before the injection of pentazocine and chronic administration of tripelennamine for 14 days did not alter pentazocine antinociceptive activity. After administration of pentazocine and tripelennamine, levels of pentazocine under concentration-time curves in the brain and plasma were slightly and significantly larger, respectively, than the levels obtained by the administration of pentazocine alone. After the administration of tripelennamine and pentazocine, the brain tripelennamine concentration at 1/4 hr was about 2.6 times that after the administration of tripelennamine alone. The results suggest that the effect of tripelennamine on pentazocine antinociception is additive; very little was through a mechanism of inhibition of pentazocine metabolism.

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Abuse of the combination of pentazocine (P) and tripelennamine (T) reputedly produces an opiate-like euphoria not obtainable from either drug alone. To determine if this effect is related to interactions at the behavioral or receptor levels we tested this combination in rats trained to discriminate morphine from saline and in mu-receptor binding assays. Displacement of 3H-DHM was compared in morphine-naive, dependent and withdrawn states to determine the importance of prior morphine exposure. The morphine training cue (3 mg/kg) generalized to P but not to T. Combinations of T (0.3 and 1.0 mg/kg) with "no effect" doses of P (1 and 3 mg/kg) resulted in greater than additive increases in morphine-like responding. 3H-DHM was displaced by P but not T in naive, dependent and withdrawn states. Specific dose combinations of T (1 nM) with P (1 nM, 10 nM, 100 nM) resulted in enhanced displacement of 3H-DHM and was not related to prior morphine exposure. We conclude that the addition of T to P increases the mu-like subjective effects of P and this effect may be due to enhanced affinity of P for the mu-receptor.

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NADPH-dependent N-demethylation of aminopyrine and tripelennamine and hydroxylation of aniline, phenytoin and tripelennamine occurred in rat gingival homogenates. The metabolic profile in gingiva appeared to be similar to that in liver, the major organ in the body for the metabolism of these xenobiotics.

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The extent of the promethazine-sensitive binding of [3H]mepyramine to a washed fraction from guinea pig cerebellum was little altered between 4 degrees and 30 degrees. The dissociation of [3H]mepyramine from the H1 receptor was markedly temperature-sensitive. An Arrhenius plot of the variation of the dissociation rate constant, k-1, with temperature was linear over the range 37 degrees -15 degrees (E alpha = 160 kJ mole-1). The association rate constant, k1, was also temperature-dependent, and an Arrhenius plot approximated well to a straight line between 30 degrees and 15 degrees (E alpha = 112 kJ mole-1). The linear relationship may hold down to 4 degrees. A consequence of the slow dissociation at 4 degrees is that the IC50 for mepyramine inhibition of promethazine-sensitive [3H]mepyramine binding at 4 degrees is independent of the concentration of [3H]mepyramine if the cerebellar homogenate is first incubated with the nonradioactive antagonist before addition of the 3H-ligand. Promethazine binding showed a temperature dependence similar to that of mepyramine, and for both antagonists and for chlorpromazine the affinity constant was not greatly increased (equal to or less than a factor of 2) at 4 degrees compared with 30 degrees. Tripelennamine showed a more rapid dissociation at 4 degrees than the other antagonists. Mequitazine dissociated slowly at 4 degrees, but the affinity constant was lower at 4 degrees than at 30 degrees.

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The quaternary ammonium-linked glucuronides of tripelennamine and cyproheptadine, important human metabolites of these drugs, were synthesized with an immobilized rabbit hepatic microsomal enzyme system as catalyst. The glucuronide of pyridine was prepared by chemical synthesis. These cationic, thermally labile, quaternary ammonium-linked glucuronides were analyzed by fast-atom bombardment mass spectrometry. The mass spectra contained intense molecular cations and characteristic losses of neutral fragments. The information contained in the spectra was sufficient to characterize the difficult-to-analyze intact quaternary ammonium glucuronides and provide structural information about the aglycon.

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Four polar metabolites were isolated from the urine of human subjects orally treated with tripelennamine, and their structures elucidated by various chemical and physical methods. One of the metabolites, which is a minor one, was identified as an N-oxide of tripelennamine, and the other three as glucuronide conjugates. One of the conjugates, which is a major metabolite, has been assigned a unique quaternary ammonium N-glucuronide structure, since it gave tripelennamine and D-glucuronic acid on incubation with beta-glucuronidase. The N-oxide, which has also been prepared synthetically, remained unchanged on similar treatment. The other two conjugates were O-glucuronides of hydroxylated derivatives, the glucuronide of hydroxytripelennamine being the principal metabolite. No desmethyltripelennamine was found in the urine, however. Hydroxylation in both cases had occurred in the pyridine ring.

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Benzyl-14C-labeled tripelennamine and its N-nitroso derivative (NDT) were administered (20 mg/kg; 50 muc/kg i.p.) separately to control and phenobarbital-pretreated rats. Tissue distribution and covalent binding of the two compounds in liver, lung, kidney, fat and muscle tissues, as well as in the plasma, were determined at 4 and 24 hours after the administration. No specific localization of the test compounds to any tissue or to the plasma was observed. The in vivo covalent binding of both the compounds to the proteins of the tissues and plasma was low; the highest binding occurred in the liver (approximately 25 pmol/mg of protein). Within 24 hours about 78% of the injected tripelennamine and its metabolites was excreted into the urine whereas only about 35% of the radioactivity of NDT was eliminated. Pretreatment with phenobarbital accelerated the elimination of both substances. The metabolites of the drug and NDT were isolated from urine, hydrolyzed by glucuronidase-sulfatase and identified as their trimethylsilyl derivatives by gas chromatography-mass spectrometry. Tripelennamine was found to be extensively metabolized by N-demethylation and aromatic hydroxylation pathways. By contrast most of the NDT was eliminated as NDT and hydroxylated metabolites; very little was excreted as N-demethylated metabolites. The hydroxylated metabolites identified were p-hydroxybenzyl, p-hydroxybenzyl-5-hydroxypyridyl and m,p-dihydroxybenzyl derivatives of the drug, its N-demethylated analog and NDT. The catechol formation with NDT was found to be 4 times that observed with tripelennamine.

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