DP Parkin, S Vandenplas, FJ Botha, ML Vandenplas, HI Seifart, PD van Helden, BJ van der Walt, PR Donald and PP van Jaarsveld
Department of Pharmacology, Faculty of Medicine, University of Stellenbosch, Tygerberg, Republic of South Africa.

The study was undertaken to show that polymorphic isoniazid elimination in humans is trimodal; that the acetylator genotype and eliminator phenotype of the individual patient are concordant; and that the differences in the pharmacokinetic parameters of fast, intermediate, and slow eliminator subgroups are statistically significant. Sixty adult patients of both sexes and of mixed race with tuberculosis participated in the trial. The apparent elimination rate constant (k, h(-1)) and the area under the isoniazid concentration-time curve (AUC, mg/L/h), over the interval 2 to 6 h after oral isoniazid were determined in all patients; NAT2 allele composition was determined in 47 patients. Serum INH concentrations were determined by HPLC and genotypes by PCR/restriction enzyme analysis. Three eliminator phenotypes could be distinguished, and concordance between the phenotype and the genotype of the individual could be demonstrated. The isoniazid concentration-time profiles of the three eliminator subgroups were significantly different (p < 0.05). The NAT2*12A allele, which codes for fast acetylation, has a high frequency in the population studied, the intermediate acetylator genotype is constituted of codominant fast and slow alleles, and the distribution of phenotypes/genotypes in the population is consistent with Hardy- Weinberg predictions. The therapeutic implications of polymorphic isoniazid metabolism are discussed.

This article has been cited by other articles:

				S. J. Gardiner and E. J. Begg Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice Pharmacol. Rev., September 1, 2006; 58(3): 521 - 590. [Abstract] [Full Text] [PDF]

				H. McIlleron, P. Wash, A. Burger, J. Norman, P. I. Folb, and P. Smith Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. Antimicrob. Agents Chemother., April 1, 2006; 50(4): 1170 - 1177. [Abstract] [Full Text] [PDF]

				C. Sholto-Douglas-Vernon, J. Sandy, T. C Victor, E. Sim, and P. D. Helden Mutational and expression analysis of tbnat and its response to isoniazid J. Med. Microbiol., December 1, 2005; 54(12): 1189 - 1197. [Abstract] [Full Text] [PDF]

				H S Schaaf, D P Parkin, H I Seifart, C J Werely, P B Hesseling, P D van Helden, J S Maritz, and P R Donald Isoniazid pharmacokinetics in children treated for respiratory tuberculosis Arch. Dis. Child., June 1, 2005; 90(6): 614 - 618. [Abstract] [Full Text] [PDF]

				M. Kinzig-Schippers, D. Tomalik-Scharte, A. Jetter, B. Scheidel, V. Jakob, M. Rodamer, I. Cascorbi, O. Doroshyenko, F. Sorgel, and U. Fuhr Should We Use N-Acetyltransferase Type 2 Genotyping To Personalize Isoniazid Doses? Antimicrob. Agents Chemother., May 1, 2005; 49(5): 1733 - 1738. [Abstract] [Full Text] [PDF]

				M. Gross, T. Kruisselbrink, K. Anderson, N. Lang, P. McGovern, R. Delongchamp, and F. Kadlubar Distribution and Concordance of N-Acetyltransferase Genotype and Phenotype in an American Population Cancer Epidemiol. Biomarkers Prev., August 1, 1999; 8(8): 683 - 692. [Abstract] [Full Text]

				P. R. DONALD, F. A. SIRGEL, F. J. BOTHA, H. I. SEIFART, D. P. PARKIN, M. L. VANDENPLAS, B. W. VAN de WAL, J. S. MARITZ, and D. A. MITCHISON The Early Bactericidal Activity of Isoniazid Related to Its Dose Size in Pulmonary Tuberculosis Am. J. Respir. Crit. Care Med., September 1, 1997; 156(3): 895 - 900. [Abstract] [Full Text] [PDF]