In vitro and in vivo disposition of 2,2-dimethyl-N-(2,4,6- trimethoxyphenyl)dodecanamide (CI-976): Identification of a novel five- carbon cleavage metabolite in rats

Drug Metabolism and Disposition

Volumn 25, Issue 1, 1997, Pages 123-130

  Sinz, Michael W ^a   Black, Ann E ^b   Bjorge, Susan M ^b   Holmes, Ann ^b   Trivedi, Bharat K ^b   Woolf, Thomas F ^b  

^a PFIZER INC   (United States)

^b NONE

Author keywords

[No Author keywords available]

Indexed keywords

2,2 DIMETHYL N (2,4,6 TRIMETHOXYPHENYL)DODECANAMIDE; CHOLESTEROL ACYLTRANSFERASE INHIBITOR;

ANIMAL CELL; ARTICLE; CHOLESTEROL BLOOD LEVEL; DRUG DISPOSITION; DRUG EFFECT; FATTY ACID OXIDATION; HYPERCHOLESTEROLEMIA; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; PEROXISOME; PRIORITY JOURNAL; RAT;

ANILIDES; ANIMALS; CELLS, CULTURED; CLOFIBRATE; CYTOCHROME P-450 ENZYME SYSTEM; ENZYME INDUCTION; FECES; FEMALE; LIVER; MALE; PHENOBARBITAL; RATS; RATS, WISTAR; STEROL O-ACYLTRANSFERASE;

EID: 0031021741     PISSN: 00909556     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (35)

1. K. E. Suckling, and E. F. Stange: Role of acyl-CoA:cholesterol acyltransferase in cellular cholesterol metabolism. J. Lipid Res. 26, 647-671 (1985).
2. D. R. Sliskovic, and A. D. White: Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents. Trends Pharmacol. Sci. 12, 194-199 (1991).
3. B. R. Krause, M. Anderson, C. L. Bisgaier, T. Bocan, R. Bousley, P. DeHart, A. Essenburg, K. Hamelehle, R. Homan, K. Kieft, W. McNally, R. Stanfield, and R. S. Newton: In vivo evidence that the lipid-regulating activity of the ACAT inhibitor CI-976 in rats is due to inhibition of intestinal and liver ACAT. J. Lipid Res. 34, 279-294 (1993).
4. B. D. Roth, C. J. Blankley, M. L. Hoefle, A. Holmes, W. H. Roark, B. K. Trivedi, A. D. Essenburg, K. A. Kieft, B. R. Krause, and R. L. Stanfield: Inhibitors of acyl-CoA:cholesterol acyltransferase. 1. Identification and structure-activity relationships of a novel series of fatty acid anilide hypocholesterolemic agents. J. Med. Chem. 35, 1609-1617 (1992).
5. T. F. Woolf, S. M. Bjorge, and T. Chang: Metabolism of the acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, CI-976: species differences in omega oxidation pathway. 8th International Symposium on Microsomes and Drug Oxidations, Stockholm, Sweden, 1990.
6. T. F. Woolf, A. Black, Y. Y. Shum, W. McNally, H. Lee, and T. Chang: Biodisposition studies with the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide, CI-976. Drug Metab. Dispos. 21, 1112-1118 (1993).
7. T. Woolf, S. Bjorge, A. Black, A. Holmes, and T. Chang: Metabolism of the acyl-CoA:cholesterol acyltransferase inhibitor 2,2-dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide in rat and monkey. Drug Metab. Dispos. 19, 696-702 (1991).
8. P. O. Seglen: Preparation of isolated rat liver cells. Methods Enzymol. 13, 29-83 (1976).
9. M. Bradford: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-255 (1976).
10. T. Omura, and R. Sato: The carbon monoxide-binding pigment of liver microsomes. J. Biol. Chem. 239, 2370-2378 (1964).
11. D. J. Harvey, and R. Mechoulam: Metabolites of cannabidiol identified in human urine. Xenobiotica 20, 303-320 (1990).
12. 6-tetrahydrocannabinol in mouse. Drug Metab. Dispos. 13, 215-219 (1985).
13. E. Samara, M. Bialer, H. Bar-On, and D. J. Harvey: Identification of metabolites of the 1″, 1″-dimethylheptyl analogue of cannabidiol in rat and dog in vivo. Xenobiotica 20, 447-455 (1990).
14. D. J. Harvey: Further studies on the oxidative cleavage of the pentyl side-chain of cannabinoids: identification of new biotransformation pathways in the metabolism of 3′-hydroxy-delta-9-tetrahydrocannabinol by the mouse. Xenobiotica 19, 1437-1447 (1989).
15. D. J. Harvey: Oxidative cleavage of the pentyl side-chain of cannabinoids. Drug Metab. Dispos. 18, 350-355 (1990).
16. J. Vamecq, and J. P. Draye: The enzymatic and mass spectrometric identification of 2-oxophytanic acid, a product of the peroxisomal oxidation of L-2-hydroxyphytanic acid. Biomed. Environ. Mass Spectrom. 15, 345-351 (1988).
17. R. J. A. Wanders, and C. W. T. Van Roermund: Studies on phytanic acid α-oxidation in rat liver and cultured human skin fibroblasts. Biochim. Biophys. Acta 1167, 345-350 (1993).
18. Y. Kawashima, N. Uy-Yu, and H. Kqauka: Sex-related difference in the inductions by perfluoro-octanoic acid of peroxisomal beta oxidation, microsomal 1-acylglycerophosphocholine acyltransferase and cytosolic long-chain acyl-CoA hydrolase in rat liver. Biochem. J. 261, 595-600 (1989).
19. S. S. Sundseth, and D. J. Waxman: Sex-dependent expression and clofibrate inducibility of cytochrome P450 4A fatty acid omega-hydroxylases. J. Biol. Chem. 267, 3915°-3921 (1992).
20. D. J. Waxman, and L. Azaroff: Phenobarbital induction of cytochrome P450 gene expression. Biochem. J. 281, 577-592 (1992).
21. R. T. Okita, and B. S. S. Masters: Effect of phenobarbital treatment and cytochrome P-450 inhibitors on the laurate ω̄-and (ω̄-1)-hydroxylase activities in rat liver microsomes. Drug Metab. Dispos. 8, 147-151 (1980).
22. G. Heinemeyer, H. Nau, A. G. Hildebrandt, and I. Roots: Oxidation and glucuronidation of valproic aid in male rats - influence of phenobarbital, 3-methylchlolanthrene, beta-naphthoflavone and clofibrate. Biochem. Pharmacol. 34, 133-139 (1985).
23. I. Close, G. Shackleton, P. S. Goldfarb, G. G. Gibson, R. Sharma, and D. Howes: Influence of single and concurrent clofibrate and phenobarbital administration on cytochrome P450-dependent mixed function oxidase activities and peroxisome proliferation in male rat liver. J. Biochem. Toxicol. 7, 193-198 (1992).
24. T. A. Kocarek, and D. R. Feller: Quantitative assessment of enzyme induction by peroxisome proliferators and application to determination of effects on triglyceride biosynthesis in primary cultures of rat hepatocytes. Biochem. Pharmacol. 38, 4169-4176 (1989).
25. R. Sharma, B. G. Lake, and G. G. Gibson: Co-induction of microsomal cytochrome P-452 and the peroxisomal fatty acid β-oxidation pathway in the rat by clofibrate and di-(2-ethylhexyl)phthalate, dose response studies. Biochem. Pharmacol. 37, 1203-1206 (1988).
26. H. Osmundsen, J. Bremer, and J. I. Pedersen: Metabolic aspects of peroxisomal beta-oxidation. Biochim. Biophys. Acta 1085, 141-158 (1991).
27. C. Skorin, C. Necochea, V. Johow, U. Soto, A. M. Grau, J. Bremer, and F. Leighton: Peroxisomal fatty acid oxidation and inhibitors of the mitochondrial carnitine palmitoyltransferase I in isolated rat hepatocytes. Biochem. J. 281, 561-567 (1992).
28. L. Agius, E. J. Meredith, and H. S. A. Sherratt: Stereospecificity of the inhibition by etomoxir of fatty acid and cholesterol synthesis in isolated rat hepatocytes. Biochem. Pharmacol. 42, 1717-1920 (1991).
29. K. F. Buechler, and J. M. Lowenstein: The involvement of carnitine intermediates in peroxisomal fatty acid oxidation: a study with 2-bromofatty acids. Arch. Biochem. Biophys. 281, 233-238 (1990).
30. M. Bronfman, M. N. Morales, L. Amigo, A. Orellana, L. Nunez, L. Cardenas, and P. C. Hidalgo: Hypolipidaemic drugs are activated to acyl-CoA esters in isolated rat hepatocytes. Biochem. J. 284, 289-295 (1992).
31. G. P. Mannearts, L. J. Debeer, J. Thomas, and P. J. De Schepper. Mitochondrial and peroxisomal fatty acid oxidation in liver homogenates and isolated hepatocytes from control and clofibrate treated rats. J. Biol. Chem. 254, 4585-4595 (1979).
32. Y. Yoshida, J. Yamado, T. Watanabe, T. Suga, and H. Takayama: Participation of the peroxisomal beta-oxidation system in the chain-shortening of PCA16, a metabolite of the cytosine arabinoside prodrug, YNK01, in rat liver. Biochem. Pharmacol. 39, 1505-1512 (1990).
33. J. Yamado, S. Ogawa, S. Hone, T. Watanabe, and T. Suga: Participation of peroxisomes in the metabolism of xenobiotic acyl compounds: comparison between peroxisomal and mitochondrial beta-oxidation of omega-phenyl fatty acids in rat liver. Biochim. Biophys. Acta 921, 292-301 (1987).
34. J. Yamada, S. Itoh, S. Hone, T. Watanabe, and T. Suga: Chain-shortening of a xenobiotic acyl compound by the peroxisomal beta-oxidation system in rat liver. Biochem. Pharmacol. 35, 4362-4368 (1986).
35. H. Suzuki, K. Mori, J. Yamada, and T. Suga: Contribution of peroxisomal beta-oxidation system to the chain-shortening of N-(α-methylbenzyl)azelaamic acid in rat liver. Biochem. Pharmacol. 39, 1975-1981 (1990).