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KINETICS AND METABOLISM OF MORPHOLINE

 

The pharmacokinetic profile, protein binding and metabolism of morpholine were studied in different species after single administration. The available studies in rat demonstrate that morpholine is rapidly and quantitatively absorbed. Morpholine has been reported to be resistant to metabolism in the rat (Tanaka et al., 1978; Sohn et al., 1982), dog (Rhodes and Case, 1977), and rabbit (Van Stee et al., 1981). In contrast, Sohn et al. (1982) reported that morpholine is extensively metabolized by N-methylation and N-oxidation in the guinea pig. Morpholine is metabolized to a much smaller extent by N-methylation in the rat and hamster (Sohn et al., 1982). Reports also suggested that morpholine is preferentially distributed to the rabbit kidney (Van Stee et al., 1981) and the rat kidney and intestine (Tanaka, 1978). Morpholine is primarily excreted unchanged in the urine.

 

Absorption

Toxicity experiments on rodents have shown that morpholine is absorbed after oral, dermal and inhalation exposure (c.f. Shea, 1939; Smyth et al., 1954).

 

Distribution

Tanaka et al. (1978) determined the distribution of 14C-labelled morpholine in male Wistar rats (3 animals/group, 250 to 300 g) after oral (200 mg/kg bw) and intravenous administration (150 mg/kg bw). The radioactivity was determined in the dried, powdered organs. Large amounts of 14C morpholine were only found in muscle and intestine regardless of route of administration. In rats sacrificed 2 hours after oral administration of morpholine HCl, 29% of the radioactivity was found in the intestine and 26% in muscle tissue. Similarly, 2 hours after intravenous injections, 19 and 27 % of the dose was found in the intestine and muscle tissue, respectively. Elimination of radioactivity from other organs, tissues and blood was very rapid in cases of both oral and i.v. administration.

Female New Zealand White rabbits were exposed to morpholine (905 mg/m³) for 5 hours by nose-only inhalation (Tombropoulos, 1979). At the end of the exposure, the animals were sacrificed and the tissue and body fluids analysed. Concentrations of Morpholine were highest in urine (324 mg/L) and kidney (118 mg/kg bw), the other tissues having concentrations below 50 mg/kg bw.

Van Stee et al. (1981) injected six male New Zealand White rabbits intravenously with 5 mmol [14C]-labelled morpholine/kg bw (435 mg/kg bw). The distribution of radioactivity after 30 min showed the highest concentrations in the renal medulla (36 mmol/kg bw) and cortex (15.4 mmol/kg bw), followed by lung (5.1 mmol/kg bw), liver (4.7 mmol/kg bw) and blood (2.3 mmol/L). Morpholine was not bound to serum proteins. Furthermore, the subcellular binding interactions of morpholine were investigated (Naylor Dana Institute, 1983). Uniform distribution of 14C in TCA-insoluble fractions indicated a non-specific binding and/or incorporation of morpholine. No significant amounts of covalently bound 14C were detected in the subcellular fractions of the liver.

 

Metabolism

Morpholine is eliminated mainly in a non-metabolized form in the urine of the rat, mouse, hamster and rabbit (Griffiths, 1968; Tanaka et al., 1978; Van Stee et al., 1981; Sohn et al., 1982). However, Sohn et al. (1982) reported that morpholine is metabolized by N-methylation followed by N-oxidation in the guinea-pig. After an intraperitoneal injection of 125 mg/kg bw [14C]-labelled Morpholine in guinea-pigs, 20 % of the radioactivity was found in the urine as N-methylmorpholine- N-oxide. The Morpholine ring can be cleaved in mammalian systems: in several studies on the metabolism of morpholine derivatives in the rat, ring cleavage products have been reported (Tatsumi et al., 1975; Hecht & Young, 1981; Kamimura et al., 1987).

 

Elimination and excretion

Expired air:

Following intraperitoneal injection, the elimination of 14C from labelled morpholine through expired air is minimal. In rats, only about 0.5 % of the dose of radioactively labeled morpholine was exhaled as 14C carbon dioxide (Sohn et al., 1981). In rabbits, only 0.0008 % of the administered morpholine dose was 14C carbon dioxide (Van Stee et al., 1981).

Urine:

Elimination studies on male Wistar rats (200-350 g) were carried out by administering morpholine HCl (500 mg/kg bw) or [14C]-labelled morpholine HCl (200 mg/kg bw) orally and morpholine-HCl (250 mg/kg bw) intravenously. In all cases, over 85 % of the total dose was excreted in urine within 24 hours. A further portion, up to 5 %, was excreted during the next three days. 14C morpholine palmitate was eliminated slightly slower, but the urinary excretion within 3 days following oral administration amounted to 90 % of the dose (Tanaka et al., 1978). Of the radioactive morpholine administered to rats, 62 to 77.5 % was excreted in the urine after 24 hours (Griffiths, 1968; Ohnishi, 1984).

The time-course of urinary excretion of 14C by Sprague-Dawley rats, Syrian golden hamsters, and strain II guinea pigs treated with 14C Morpholine was compared by Sohn et al. (1982). In all three species over 80 % of the dose was excreted in 3 days, while the rate of urinary excretion within the first 6 hours was greatest in the hamster and least in the guinea pig.

Van Stee et al. (1981) infused rabbits intravenously with 14C morpholine (5 mmol/kg bw) which had been neutralized with HCl. After 4 hours, 18.5 % of the dose was excreted in the urine. When the pH of the urine was lowered from 7.8 - 7.9 to 7.1 - 7.2 by administration of ammonium chloride (10 g/L) in drinking-water prior to the Morpholine injection, the urinary excretion more than doubled (to 43 %). These data suggest that the urinary excretion of morpholine is enhanced by its neutralization with acid.

14C Morpholine was administered to dogs by an unspecified route. 70 to 80 % of the radioactive morpholine was excreted in the urine, with no other detectable metabolites (Rhodes & Case, 1977).

Faeces:

Rats dosed orally or intravenously with morpholine HCl excreted not more than 1.7 % of the dose in the faeces (Griffiths, 1968; Tanaka et al., 1978). However, when dosed orally with morpholine palmitate (Tanaka et al., 1978; Ohnishi, 1984), up to 7% was excreted in faeces.

 

Retention and turnover

Plasma concentration-time curves of 14C after intraperitoneal injections of 14C Morpholine (125 mg/kg bw in 0.9% NaCl) in Sprague-Dawley rats, Syrian golden hamsters, and strain II guinea pigs declined biexponentially. Marked differences were noted between the guinea pig and the other two species with respect to plasma levels (as well as the metabolism of Morpholine). Whereas rates of the first phase of elimination from plasma in rats and hamsters were similar (half-lives of 115 and 120 min, respectively), the half-life in guinea-pigs was significantly longer (300 min) (Sohn et al., 1982).

 

Additional information on Morpholine – nitrosation

In the presence of nitrite, Morpholine can be nitrosated to the carcinogenic N-nitrosomorpholine (NMOR). For instance, NMOR was found in the stomach of rodents whose feed contained nitrite and Morpholine (Sander et al., 1968; Inui et al., 1978; Kitano et al., 1979). Hecht & Morrison (1984) developed a method to monitor the in vivo formation of NMOR by measuring N-nitroso(2 -hydroxyethyl)glycine, its major urinary metabolite. The formation of NMOR was measured in F-344 rats over wide range of doses of Morpholine (38.3 - 0.92 µmol) and sodium nitrite (191 - 4.8 µmol). According to estimates by the authors, 0.5 to 12 % of the administered Morpholine, depending on the dose, was nitrosated. Furthermore, in vitro experiments have demonstrated that nitrosation of Morpholine is also possible in human saliva and in gastric juices (Ziebarth, 1997; Ziebarth, 1973; Boyland et al., 1971).

 

 

LITERATURE

 

Boyland E, Nice E & Williams K (1971). The catalysis of nitrosation by thiocyanate from saliva. Food Cosmet. Toxicol. 9: 639 -643

 

Griffiths MH (1968). The metabolism of N-triphenylmethylmorpholine in the dog and rat. Biochem. J. 108: 731 -740

 

Hecht SS & Morrison JB (1984). A sensitive method for detecting in vivo formation of N-nitrosomorpholine and its application to rats given low doses of Morpholine and sodium nitrite. Cancer Res. 7: 2873 -2877

 

Hecht SS & Young R (1981). Metabolic alpha-hydroxylation of N-nitrosomorpholine and 3,3,5,5 -tetradeutero-N-nitrosomorpholine in the F344 rat. Cancer Res. 41: 5039 -5043

 

Inui N, Nishi Y, Taketomi M & Yamada T (1978). A short-term, simple method for detection of N-nitroso compounds produced from sodium nitrite and Morpholine in stomach. Biochem. Biophys. Res. Commun. 81: 310 -314

 

Kamimura H, Enjoji Y, Sasaki H, Kawai R, Kaniwa H, Niigata K & Kageyama S (1987). Disposition and metabolism of indeloxazine hydrochloride, a cerebral activator, in rats. Xenobiotica 17: 645 -658

 

Kitano ML, Takada N, Chen T, Ito H, Nomura T, Tsuda H, Wild CP & Fukushima S (1997). Carcinogenicity of Methylurea or Morpholine in Combination with Sodium Nitrite in a Rat Multi-organ Carcinogenesis Bioassay. Jpn. J. Cancer Res. 88: 797-806.

 

Naylor Dana Institute (1983). Metabolism and Disposition of Morpholine. Division of Molecular Biology and Pharmacology, Naylor Dana Institute for Disease Prevention, American Health Foundation. Unpublished study report.

 

Ohnishi T (1984). Morpholine. Studies on mutagenicity of the food additive Morpholine (fatty acid salt). Nippon Eiseigaku Zasski 39: 729-745 (in Japanese with English summary)

 

Rhodes C & Case DE (1977). Non-metabolite residues of ICI 58,834 (viloxazine). Studies with (14C)Morpholine, (14C)ethanolamine and (14C)glyoxylate. Xenobiotica 7: 112

 

Sander J, Schweinsberg F & Menz H-P (1968). Untersuchungen über die Entstehung cancerogener Nitrosamine im Magen. Hoppe-Seyler's Z. Physiol. Chem. 349: 1691 -1697

 

Shea TE Jr (1939). The acute and sub-acute toxicity of Morpholine. J. Ind. Hyg. Toxicol. 21: 236 -245

 

Smyth HF Jr, Carpenter CP, Weil CS & Pozzani UC (1954). Range-finding toxicity data. Arch. Ind. Hyg. Occup. Med. 10: 61 -68

 

Sohn OS, Fiala ES, Conaway CC & Weisburger JH (1982). Metabolism and disposition of Morpholine in the rat, hamster and guinea pig. Toxicol. Appl. Pharmacol. 64: 486 -491

 

Tanaka A,Tokieda T, Nambaru S, Osawa M & Yamaha T (1978). Excretion and distribution of Morpholine salts in rats. J. Food Hyg. Soc. 19: 329 -334

 

Tatsumi K, Kitamura S, Yoshimura Y, Tanaka S, Hashimoto K & Igarashi T (1975). The metabolism of phenyl o-(2-N-morpholinoethoxy)-phenyl ether hydrochloride in the rabbit and rat. Xenobiotica 5: 377 -388

 

Tombropoulos EG (1979). Micromethod for the gas chromatographic determination of Morpholine in biological tissues and fluids. J. Chromatogr. 164: 95 -99

 

Van Stee EW, Wynns PC & Moorman MP (1981). Distribution and disposition of Morpholine in the rabbit. Toxicology 20: 53 -60

 

Ziebarth D (1973). N-nitrosation of secondary amines and particularly of drugs, in buffer solutions and human gastric juice. IARC Sci. Publ. 9: 137-141

 

Ziebarth D, Spiegelhalder B & Bartsch H (1997). N-nitrosation of medicinal drugs catalysed by bacteria from human saliva and gastro-intestinal tract, including Helicobacter pylori. Carcinogenesis 18: 383 -389