Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 May;40(5):1231–1236. doi: 10.1128/aac.40.5.1231

Zidovudine, trimethoprim, and dapsone pharmacokinetic interactions in patients with human immunodeficiency virus infection.

B L Lee 1, S Safrin 1, V Makrides 1, J G Gambertoglio 1
PMCID: PMC163297  PMID: 8723472

Abstract

Zidovudine is widely prescribed for the treatment of human immunodeficiency virus (HIV) infection. Trimethoprim and dapsone are commonly used in the management of Pneumocystis carinii pneumonia in HIV-infected patients. To examine the pharmacokinetic interactions among these drugs, eight HIV-infected patients (26 to 43 years old) with a mean CD4 count of 524.4 +/- 405.7 cells per mm3 received zidovudine (200 mg), trimethoprim (200 mg), and dapsone (100 mg) as single agents and in two- and three-drug combinations. Blood and urine samples were collected at a specified time and analyzed for zidovudine, zidovudine-glucuronide, trimethoprim, dapsone, and monoacetyl-dapsone concentrations under single-dose and steady-state conditions. Zidovudine did not influence the pharmacokinetic disposition of dapsone or trimethoprim. Dapsone had no effect on the pharmacokinetic disposition of zidovudine. Trimethoprim significantly decreased the renal clearance of zidovudine by 58% (5.0 +/- 1.8 versus 2.1 +/- 0.5 ml/min/kg of body weight [P < 0.05]). There was a concurrent 54% decrease in the mean urinary recovery of zidovudine (11.7 +/- 3.5 versus 5.4 +/- 3.0 [P < 0.05]), and the metabolic ratio was decreased by 78% (0.32 +/- 0.4 versus 0.07 +/- 0.05 [P < 0.05]). The mean area under the concentration-time curve from 0 to 6 h of the zidovudine-glucuronide/ zidovudine ratio was unchanged. We conclude that zidovudine, trimethoprim, and dapsone can be coadministered to patients with AIDS without significant pharmacokinetic interaction. However, in AIDS patients with liver impairment and impaired glucuronidation, doses of zidovudine may need to be decreased.

Full Text

The Full Text of this article is available as a PDF (213.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahmad R. A., Rogers H. J. Pharmacokinetics and protein binding interactions of dapsone and pyrimethamine. Br J Clin Pharmacol. 1980 Nov;10(5):519–524. doi: 10.1111/j.1365-2125.1980.tb01798.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bowden F. J., Harman P. J., Lucas C. R. Serum trimethoprim and sulphamethoxazole levels in AIDS. Lancet. 1986 Apr 12;1(8485):853–853. doi: 10.1016/s0140-6736(86)90958-x. [DOI] [PubMed] [Google Scholar]
  3. Chatton J. Y., Munafo A., Chave J. P., Steinhäuslin F., Roch-Ramel F., Glauser M. P., Biollaz J. Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide. Br J Clin Pharmacol. 1992 Dec;34(6):551–554. [PMC free article] [PubMed] [Google Scholar]
  4. Child S., Montaner J., Tsoukas C., Fanning M., Le T., Wall R. A., Ruedy J. Canadian multicenter azidothymidine trial: AZT pharmacokinetics. J Acquir Immune Defic Syndr. 1991;4(9):865–870. [PubMed] [Google Scholar]
  5. Cload P. A. A review of the pharmacokinetics of zidovudine in man. J Infect. 1989 Jan;18 (Suppl 1):15–21. doi: 10.1016/s0163-4453(89)80076-3. [DOI] [PubMed] [Google Scholar]
  6. Gelber R., Peters J. H., Gordon G. R., Glazko A. J., Levy L. The polymorphic acetylation of dapsone in man. Clin Pharmacol Ther. 1971 Mar-Apr;12(2):225–238. doi: 10.1002/cpt1971122part1225. [DOI] [PubMed] [Google Scholar]
  7. Ghezzi P., Saccardo B., Bianchi M. Recombinant tumor necrosis factor depresses cytochrome P450-dependent microsomal drug metabolism in mice. Biochem Biophys Res Commun. 1986 Apr 14;136(1):316–321. doi: 10.1016/0006-291x(86)90912-5. [DOI] [PubMed] [Google Scholar]
  8. Good S. S., Reynolds D. J., de Miranda P. Simultaneous quantification of zidovudine and its glucuronide in serum by high-performance liquid chromatography. J Chromatogr. 1988 Sep 23;431(1):123–133. doi: 10.1016/s0378-4347(00)83075-3. [DOI] [PubMed] [Google Scholar]
  9. Gordin F. M., Simon G. L., Wofsy C. B., Mills J. Adverse reactions to trimethoprim-sulfamethoxazole in patients with the acquired immunodeficiency syndrome. Ann Intern Med. 1984 Apr;100(4):495–499. doi: 10.7326/0003-4819-100-4-495. [DOI] [PubMed] [Google Scholar]
  10. Hansen J. M., Kampmann J. P., Siersbaek-Nielsen K., Lumholtz I. B., Arrøe M., Abildgaard U., Skovsted L. The effect of different sulfonamides on phenytoin metabolism in man. Acta Med Scand Suppl. 1979;624:106–110. doi: 10.1111/j.0954-6820.1979.tb00729.x. [DOI] [PubMed] [Google Scholar]
  11. Hengstmann J. H. Pharmacokinetics of trimethoprim and tetroxoprim. A review. Antibiot Chemother (1971) 1982;31:211–225. doi: 10.1159/000400134. [DOI] [PubMed] [Google Scholar]
  12. Hughes W. T., Feldman S., Chaudhary S. C., Ossi M. J., Cox F., Sanyal S. K. Comparison of pentamidine isethionate and trimethoprim-sulfamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Pediatr. 1978 Feb;92(2):285–291. doi: 10.1016/s0022-3476(78)80028-6. [DOI] [PubMed] [Google Scholar]
  13. Hutabarat R. M., Unadkat J. D., Sahajwalla C., McNamara S., Ramsey B., Smith A. L. Disposition of drugs in cystic fibrosis. I. Sulfamethoxazole and trimethoprim. Clin Pharmacol Ther. 1991 Apr;49(4):402–409. doi: 10.1038/clpt.1991.47. [DOI] [PubMed] [Google Scholar]
  14. Kaufman J. M., Fauver H. E., Jr Potentiation of warfarin by trimethoprim-sulfamethoxazole. Urology. 1980 Dec;16(6):601–603. doi: 10.1016/0090-4295(80)90568-3. [DOI] [PubMed] [Google Scholar]
  15. Kornhauser D. M., Petty B. G., Hendrix C. W., Woods A. S., Nerhood L. J., Bartlett J. G., Lietman P. S. Probenecid and zidovudine metabolism. Lancet. 1989 Aug 26;2(8661):473–475. doi: 10.1016/s0140-6736(89)92087-4. [DOI] [PubMed] [Google Scholar]
  16. Kosoglou T., Rocci M. L., Jr, Vlasses P. H. Trimethoprim alters the disposition of procainamide and N-acetylprocainamide. Clin Pharmacol Ther. 1988 Oct;44(4):467–477. doi: 10.1038/clpt.1988.181. [DOI] [PubMed] [Google Scholar]
  17. Lee B. L., Medina I., Benowitz N. L., Jacob P., 3rd, Wofsy C. B., Mills J., 5th Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of Pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). Evidence of drug interactions. Ann Intern Med. 1989 Apr 15;110(8):606–611. doi: 10.7326/0003-4819-110-8-606. [DOI] [PubMed] [Google Scholar]
  18. Lee B. L., Wong D., Benowitz N. L., Sullam P. M. Altered patterns of drug metabolism in patients with acquired immunodeficiency syndrome. Clin Pharmacol Ther. 1993 May;53(5):529–535. doi: 10.1038/clpt.1993.66. [DOI] [PubMed] [Google Scholar]
  19. Lähdevirta J., Maury C. P., Teppo A. M., Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med. 1988 Sep;85(3):289–291. doi: 10.1016/0002-9343(88)90576-1. [DOI] [PubMed] [Google Scholar]
  20. May D. G., Porter J. A., Uetrecht J. P., Wilkinson G. R., Branch R. A. The contribution of N-hydroxylation and acetylation to dapsone pharmacokinetics in normal subjects. Clin Pharmacol Ther. 1990 Dec;48(6):619–627. doi: 10.1038/clpt.1990.204. [DOI] [PubMed] [Google Scholar]
  21. Medina I., Mills J., Leoung G., Hopewell P. C., Lee B., Modin G., Benowitz N., Wofsy C. B. Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone. N Engl J Med. 1990 Sep 20;323(12):776–782. doi: 10.1056/NEJM199009203231202. [DOI] [PubMed] [Google Scholar]
  22. Patel R. B., Welling P. G. Clinical pharmacokinetics of co-trimoxazole (trimethoprim-sulphamethoxazole). Clin Pharmacokinet. 1980 Sep-Oct;5(5):405–423. doi: 10.2165/00003088-198005050-00001. [DOI] [PubMed] [Google Scholar]
  23. Petersen P., Kastrup J., Bartram R., Mølholm Hansen J. Digoxin-trimethoprim interaction. Acta Med Scand. 1985;217(4):423–427. doi: 10.1111/j.0954-6820.1985.tb02718.x. [DOI] [PubMed] [Google Scholar]
  24. Reddy M. M., Sorrell S. J., Lange M., Grieco M. H. Tumor necrosis factor and HIV P24 antigen levels in serum of HIV-infected populations. J Acquir Immune Defic Syndr. 1988;1(5):436–440. [PubMed] [Google Scholar]
  25. Sahai J., Gallicano K., Garber G., Pakuts A., Hawley-Foss N., Huang L., McGilveray I., Cameron D. W. Evaluation of the in vivo effect of naproxen on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus. Clin Pharmacol Ther. 1992 Nov;52(5):464–470. doi: 10.1038/clpt.1992.173. [DOI] [PubMed] [Google Scholar]
  26. Sattler F. R., Cowan R., Nielsen D. M., Ruskin J. Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A prospective, noncrossover study. Ann Intern Med. 1988 Aug 15;109(4):280–287. doi: 10.7326/0003-4819-109-4-280. [DOI] [PubMed] [Google Scholar]
  27. Singlas E., Pioger J. C., Taburet A. M., Colaneri S., Fillastre J. P. Comparative pharmacokinetics of zidovudine (AZT) and its metabolite (G.AZT) in healthy subjects and HIV seropositive patients. Eur J Clin Pharmacol. 1989;36(6):639–640. doi: 10.1007/BF00637752. [DOI] [PubMed] [Google Scholar]
  28. Spreux-Varoquaux O., Chapalain J. P., Cordonnier P., Advenier C., Pays M., Lamine L. Determination of trimethoprim, sulphamethoxazole and its N4-acetyl metabolite in biological fluids by high-performance liquid chromatography. J Chromatogr. 1983 May 13;274:187–199. doi: 10.1016/s0378-4347(00)84422-9. [DOI] [PubMed] [Google Scholar]
  29. Stevens R. C., Laizure S. C., Sanders P. L., Stein D. S. Multiple-dose pharmacokinetics of 12 milligrams of trimethoprim and 60 milligrams of sulfamethoxazole per kilogram of body weight per day in healthy volunteers. Antimicrob Agents Chemother. 1993 Mar;37(3):448–452. doi: 10.1128/aac.37.3.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vergin H., Ferber H., Zimmermann I., Neurath G. B. Single and multiple dose kinetics of co-tetroxazine and co-trimoxazole in patients. Int J Clin Pharmacol Ther Toxicol. 1981 Aug;19(8):350–357. [PubMed] [Google Scholar]
  31. Weber W. W., Hein D. W. N-acetylation pharmacogenetics. Pharmacol Rev. 1985 Mar;37(1):25–79. [PubMed] [Google Scholar]
  32. Wing L. M., Miners J. O. Cotrimoxazole as an inhibitor of oxidative drug metabolism: effects of trimethoprim and sulphamethoxazole separately and combined on tolbutamide disposition. Br J Clin Pharmacol. 1985 Nov;20(5):482–485. doi: 10.1111/j.1365-2125.1985.tb05102.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Winston D. J., Lau W. K., Gale R. P., Young L. S. Trimethoprim-sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med. 1980 Jun;92(6):762–769. doi: 10.7326/0003-4819-92-6-762. [DOI] [PubMed] [Google Scholar]
  34. Wormser G. P., Keusch G. T., Heel R. C. Co-trimoxazole (trimethoprim-sulfamethoxazole): an updated review of its antibacterial activity and clinical efficacy. Drugs. 1982 Dec;24(6):459–518. doi: 10.2165/00003495-198224060-00002. [DOI] [PubMed] [Google Scholar]
  35. Zuidema J., Hilbers-Modderman E. S., Merkus F. W. Clinical pharmacokinetics of dapsone. Clin Pharmacokinet. 1986 Jul-Aug;11(4):299–315. doi: 10.2165/00003088-198611040-00003. [DOI] [PubMed] [Google Scholar]
  36. de Miranda P., Good S. S., Yarchoan R., Thomas R. V., Blum M. R., Myers C. E., Broder S. Alteration of zidovudine pharmacokinetics by probenecid in patients with AIDS or AIDS-related complex. Clin Pharmacol Ther. 1989 Nov;46(5):494–500. doi: 10.1038/clpt.1989.176. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES