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. 1996 Dec;40(12):2749–2755. doi: 10.1128/aac.40.12.2749

Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs.

K Hosoe 1, T Mae 1, E Konishi 1, K Fujii 1, K Yamashita 1, T Yamane 1, T Hidaka 1, T Ohashi 1
PMCID: PMC163615  PMID: 9124834

Abstract

The pharmacokinetics of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin (KRM-1648) in rats and dogs given a single oral dose of 3, 30, or 100 mg/kg of body weight were studied. In the rats, the concentrations of KRM-1648 in plasma, whole blood, and tissues peaked between 2.0 and 24.0 h, with elimination half-lives ranging from 6.2 to 19.5 h. The peak concentrations and the areas under the concentration-versus-time curves (AUC) for whole blood and tissues were 2 to 277 times higher than those for plasma. The high levels of KRM-1648 in tissues were consistent with its large volume of distribution (in excess of 10 liters/kg). A nonlinear increase in peak concentrations and AUCs for plasma, whole blood, and tissues occurred as the dose was increased and was consistent with the dose-dependent decrease in bioavailability. In the dogs, KRM-1648 levels in plasma and whole blood also exhibited a late time to the peak concentration (ranging from 4.0 to 11.2 h), a long elimination half-life (ranging from 15.2 to 24.0 h), and nonlinear kinetics. KRM-1648 exhibited high levels of plasma protein binding (more than 99%) and a high degree of affinity for lipoproteins in the plasma of both animals. After administration of KRM-1648, measurable levels of its metabolites, 25-deacetyl KRM-1648 in rats and 25-deacetyl KRM-1648 and 30-hydroxy KRM-1648 in dogs, were found in the biological samples tested. Thus, KRM-1648 is characterized by a high tissue affinity, a long elimination half-life, and nonlinear pharmacokinetics.

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Selected References

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  1. Allain C. C., Poon L. S., Chan C. S., Richmond W., Fu P. C. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed] [Google Scholar]
  2. Bermudez L. E., Wu M., Young L. S. Intracellular killing of Mycobacterium avium complex by rifapentine and liposome-encapsulated amikacin. J Infect Dis. 1987 Sep;156(3):510–513. doi: 10.1093/infdis/156.3.510. [DOI] [PubMed] [Google Scholar]
  3. Chapman M. J., Goldstein S., Lagrange D., Laplaud P. M. A density gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum. J Lipid Res. 1981 Feb;22(2):339–358. [PubMed] [Google Scholar]
  4. Emori M., Saito H., Sato K., Tomioka H., Setogawa T., Hidaka T. Therapeutic efficacy of the benzoxazinorifamycin KRM-1648 against experimental Mycobacterium avium infection induced in rabbits. Antimicrob Agents Chemother. 1993 Apr;37(4):722–728. doi: 10.1128/aac.37.4.722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Glasson S., Zini R., Tillement J. P. Multiple human serum binding of two thienopyridinic derivatives, ticlopidine and PCR 2362, and their distribution between HSA, alpha1-acid glycoprotein and lipoproteins. Biochem Pharmacol. 1982 Mar 1;31(5):831–835. doi: 10.1016/0006-2952(82)90470-1. [DOI] [PubMed] [Google Scholar]
  6. Hosoe K., Konishi E., Hidaka T., Yamane T., Yamashita K., Ohashi T. High-performance liquid chromatographic determination of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl)benzoxazinorifamycin (KRM-1648) and its deacetyl metabolite in plasma, whole blood, urine and tissue samples in rats. J Chromatogr B Biomed Appl. 1994 Mar 4;653(2):177–186. doi: 10.1016/0378-4347(93)e0431-o. [DOI] [PubMed] [Google Scholar]
  7. Hosoe K., Mae T., Yamashita K., Fujii K., Yamane T., Hidaka T., Ohashi T. Identification and antimicrobial activity of urinary metabolites of a rifamycin derivative in dog. Xenobiotica. 1996 Mar;26(3):321–332. doi: 10.3109/00498259609046711. [DOI] [PubMed] [Google Scholar]
  8. Inderlied C. B., Barbara-Burnham L., Wu M., Young L. S., Bermudez L. E. Activities of the benzoxazinorifamycin KRM 1648 and ethambutol against Mycobacterium avium complex in vitro and in macrophages. Antimicrob Agents Chemother. 1994 Aug;38(8):1838–1843. doi: 10.1128/aac.38.8.1838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Klemens S. P., Cynamon M. H. Activity of KRM-1648 in combination with isoniazid against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother. 1996 Feb;40(2):298–301. doi: 10.1128/aac.40.2.298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Koch-Weser J., Sellers E. M. Binding of drugs to serum albumin (first of two parts). N Engl J Med. 1976 Feb 5;294(6):311–316. doi: 10.1056/NEJM197602052940605. [DOI] [PubMed] [Google Scholar]
  11. Kuze F., Yamamoto T., Amitani R., Suzuki K. [In vivo activities of new rifamycin derivatives against mycobacteria]. Kekkaku. 1991 Jan;66(1):7–12. [PubMed] [Google Scholar]
  12. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  13. Lemaire M., Tillement J. P. Role of lipoproteins and erythrocytes in the in vitro binding and distribution of cyclosporin A in the blood. J Pharm Pharmacol. 1982 Nov;34(11):715–718. doi: 10.1111/j.2042-7158.1982.tb06206.x. [DOI] [PubMed] [Google Scholar]
  14. Luna-Herrera J., Reddy M. V., Gangadharam P. R. In vitro activity of the benzoxazinorifamycin KRM-1648 against drug-susceptible and multidrug-resistant tubercle bacilli. Antimicrob Agents Chemother. 1995 Feb;39(2):440–444. doi: 10.1128/aac.39.2.440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Nightingale S. D., Cameron D. W., Gordin F. M., Sullam P. M., Cohn D. L., Chaisson R. E., Eron L. J., Sparti P. D., Bihari B., Kaufman D. L. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infection in AIDS. N Engl J Med. 1993 Sep 16;329(12):828–833. doi: 10.1056/NEJM199309163291202. [DOI] [PubMed] [Google Scholar]
  16. Rudman D., Hollins B., Bixler T. J., 2nd, Mosteller R. C. Transport of drugs, hormones and fatty acids in lipemic serum. J Pharmacol Exp Ther. 1972 Mar;180(3):797–810. [PubMed] [Google Scholar]
  17. Saito H., Tomioka H., Sato K., Emori M., Yamane T., Yamashita K., Hosoe K., Hidaka T. In vitro antimycobacterial activities of newly synthesized benzoxazinorifamycins. Antimicrob Agents Chemother. 1991 Mar;35(3):542–547. doi: 10.1128/aac.35.3.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Takayama M., Itoh S., Nagasaki T., Tanimizu I. A new enzymatic method for determination of serum choline-containing phospholipids. Clin Chim Acta. 1977 Aug 15;79(1):93–98. doi: 10.1016/0009-8981(77)90465-x. [DOI] [PubMed] [Google Scholar]
  19. Tomioka H., Saito H., Sato K., Yamane T., Yamashita K., Hosoe K., Fujii K., Hidaka T. Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice. Antimicrob Agents Chemother. 1992 Feb;36(2):387–393. doi: 10.1128/aac.36.2.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Urien S., Riant P., Albengres E., Brioude R., Tillement J. P. In vitro studies on the distribution of probucol among human plasma lipoproteins. Mol Pharmacol. 1984 Sep;26(2):322–327. [PubMed] [Google Scholar]
  21. Weinkam R. J., Finn A., Levin V. A., Kane J. P. Lipophilic drugs and lipoproteins: partitioning effects on chloroethylnitrosourea reaction rates in serum. J Pharmacol Exp Ther. 1980 Aug;214(2):318–323. [PubMed] [Google Scholar]
  22. Woodley C. L., Kilburn J. O. In vitro susceptibility of Mycobacterium avium complex and Mycobacterium tuberculosis strains to a spiro-piperidyl rifamycin. Am Rev Respir Dis. 1982 Sep;126(3):586–587. doi: 10.1164/arrd.1982.126.3.586. [DOI] [PubMed] [Google Scholar]
  23. Yamamoto T., Amitani R., Kuze F., Suzuki K. [In vitro activities of new rifamycin derivatives against Mycobacterium tuberculosis and M. avium complex]. Kekkaku. 1990 Dec;65(12):805–810. [PubMed] [Google Scholar]
  24. Yamamoto T., Amitani R., Suzuki K., Tanaka E., Murayama T., Kuze F. Activity of KRM-1648 alone or in combination with both ethambutol and kanamycin or clarithromycin against Mycobacterium intracellulare infections in beige mice. Antimicrob Agents Chemother. 1996 Feb;40(2):429–432. doi: 10.1128/aac.40.2.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Yamamoto T., Amitani R., Suzuki K., Tanaka E., Murayama T., Kuze F. In vitro bactericidal and in vivo therapeutic activities of a new rifamycin derivative, KRM-1648, against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1996 Feb;40(2):426–428. doi: 10.1128/aac.40.2.426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Yamane T., Hashizume T., Yamashita K., Konishi E., Hosoe K., Hidaka T., Watanabe K., Kawaharada H., Yamamoto T., Kuze F. Synthesis and biological activity of 3'-hydroxy-5'-aminobenzoxazinorifamycin derivatives. Chem Pharm Bull (Tokyo) 1993 Jan;41(1):148–155. doi: 10.1248/cpb.41.148. [DOI] [PubMed] [Google Scholar]

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