Background. Analysis of isoniazid (INH) uptake has been based on measurement of plasma concentrations providing a short-term and potentially biased view. Objectives. To establish hair analysis as a tool to measure long-term uptake of INH and to assess whether acetylator phenotype in hair reflects N-acetyltransferase-2 (NAT2) genotype. Design and Methods. INH and acetyl-INH concentrations in hair were determined in patients on INH treatment for M. tuberculosis infection using high pressure liquid chromatography/mass spectrometry. Acetyl-INH/INH ratios were correlated with NAT-2 genotype. Results. Hair concentrations of INH, determined in 40 patients, were not dependent on ethnic group or body mass index and were significantly higher in male compared to female patients (median (range) 2.37？ng/mg (0.76–4.9) versus 1.11？ng/mg (0.02–7.20) ( ). Acetyl-INH/INH ratios were a median of 15.2% (14.5 to 31.7) in homozygous rapid acetylator NAT-2 genotype and 37.3% (1.73 to 51.2) in the heterozygous rapid acetylator NAT-2 genotype and both significantly higher than in the slow acetylator NAT-2 genotype with 5.8% (0.53 to 14.4) ( ). Conclusions. Results of hair analysis for INH showed lower concentrations in females. Acetyl-INH/INH ratios were significantly lower in patients with slow acetylator versus rapid acetylator genotypes. 1. Introduction The first application of hair analysis in monitoring of anti-infective treatment was the measurement of hair concentrations of indinavir, a protease inhibitor, in patients with HIV infection. Indinavir hair concentrations were significantly higher in responders compared to nonresponders [1]. Previous studies analysed antiepileptic drugs in segments of hair of patients on treatment for epilepsy and found that variability of hair drug concentrations, reflecting variable antiepileptic drug ingestion over time, was greater in epileptic patients with sudden unexplained death [2]. Hair analysis in patients on carbamazepine for treatment of epilepsy showed a significant linear relationship between the prescribed dose, hair concentration, and total plasma concentration [3]. Failure of tuberculosis treatment and relapse of tuberculosis, with selection of drug resistance mutations, have not been associated with low maximum concentrations of antituberculosis drugs such as isoniazid (INH). These conditions have been, however, associated with low areas under the concentration curve (AUC) in plasma, which is found in patients with intermittent noncompliance to treatment, widely spaced intermittent therapy, and chronically reduced
References
[1]
L. Bernard, A. Vuagnat, G. Peytavin et al., “Relationship between levels of indinavir in hair and virologic response to highly active antiretroviral therapy,” Annals of Internal Medicine, vol. 137, no. 8, pp. 656–659, 2002.
[2]
J. Williams, C. Lawthom, F. D. Dunstan, et al., “Variability of antiepileptic meditation taking behaviour in sudden unexplained death in epilepsy: hair analysis at autopsy,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 77, no. 6, pp. 481–484, 2006.
[3]
J. Williams, P. N. Patsalos, and J. F. Wilson, “Hair analysis as a potential index of therapeutic compliance in the treatment of epilepsy,” Forensic Science International, vol. 84, no. 1–3, pp. 113–122, 1997.
[4]
P. R. Donald, D. P. Parkin, H. I. Seifart et al., “The influence of dose and N-acetyltransferase-2 (NAT2) genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid,” European Journal of Clinical Pharmacology, vol. 63, no. 7, pp. 633–639, 2007.
[5]
P. Gurumurthy, G. Ramachandran, A. K. H. Kumar et al., “Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease,” Antimicrobial Agents and Chemotherapy, vol. 48, no. 11, pp. 4473–4475, 2004.
[6]
M. Weiner, W. Burman, A. Vernon et al., “Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine,” American Journal of Respiratory and Critical Care Medicine, vol. 167, no. 10, pp. 1341–1347, 2003.
[7]
H. S. Schaaf, D. P. Parkin, H. I. Seifart et al., “Isoniazid pharmacokinetics in children treated for respiratory tuberculosis,” Archives of Disease in Childhood, vol. 90, no. 6, pp. 614–618, 2005.
[8]
M. Kinzig-Schippers, D. Tomalik-Scharte, A. Jetter et al., “Should we use N-acetyltransferase type 2 genotyping to personalize isoniazid doses?” Antimicrobial Agents and Chemotherapy, vol. 49, no. 5, pp. 1733–1738, 2005.
[9]
M. Weiner, D. Benator, W. Burman et al., “Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis,” Clinical Infectious Diseases, vol. 40, no. 10, pp. 1481–1491, 2005.
[10]
S. Paranjothy, M. Eisenhut, M. Lilley et al., “Extensive transmission of Mycobacterium tuberculosis from 9 year old child with pulmonary tuberculosis and negative sputum smear,” British Medical Journal, vol. 337, p. a1184, 2008.
[11]
O. Braun-Falco and G. P. Heilgemeir, “The trichogram,” SEM for Dermatologists, vol. 4, article 40, 1985.
[12]
K. Anslinger, B. Bayer, B. Rolf, W. Keil, and W. Eisenmenger, “Application of the BioRobot EZ1 in a forensic laboratory,” Legal Medicine, vol. 7, no. 3, pp. 164–168, 2005.
[13]
A. Khedhaier, E. Hassen, N. Bouaouina, S. Gabbouj, S. B. Ahmed, and L. Chouchane, “Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) polymorphisms in breast carcinoma,” BMC Cancer, vol. 8, article 109, 2008.
[14]
K. Fukino, Y. Sasaki, S. Hirai et al., “Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients,” Journal of Toxicological Sciences, vol. 33, no. 5, pp. 187–195, 2008.
[15]
A. Pariente-Khayat, E. Rey, D. Gendrel et al., “Isoniazid acetylation metabolic ratio during maturation in children,” Clinical Pharmacology and Therapeutics, vol. 62, no. 4, pp. 377–383, 1997.
[16]
O. Paulsen and L. G. Nilsson, “Distribution of acetylator phenotype in relation to age and sex in Swedish patients. A retrospective study,” European Journal of Clinical Pharmacology, vol. 28, no. 3, pp. 311–315, 1985.
[17]
P. R. Gangadharam, A. L. Bhatia, S. Radhakrishna, and J. B. Selkon, “Rate of inactivation of isoniazid in South Indian patients with pulmonary tuberculosis,” Bulletin of the World Health Organization, vol. 25, pp. 765–777, 1961.
[18]
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,” Antimicrobial Agents and Chemotherapy, vol. 50, no. 4, pp. 1170–1177, 2006.
[19]
J. E. Conte, J. A. Golden, M. McQuitty et al., “Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid,” Antimicrobial Agents and Chemotherapy, vol. 46, no. 8, pp. 2358–2364, 2002.
[20]
H. Mcllleron, M. Willemse, C. J. Werely et al., “Isoniazid plasma concentrations in a cohort of South African children with tuberculosis: implications for international pediatric dosing guidelines,” Clinical Infectious Diseases, vol. 48, no. 11, pp. 1547–1553, 2009.
[21]
D. A. Evans, P. B. Storey, and V. A. Mckusick, “Further observations on the determination of the isoniazid inactivator phenotype,” Bulletin of the Johns Hopkins Hospital, vol. 108, pp. 60–66, 1961.
[22]
V. G. F. Pinheiro, L. M. A. Ramos, H. A. S. Monteiro, et al., “Intestinal permeability and malabsorption of rifamicin and INH in active pulmonary tuberculosis,” Brazilian Journal of Infectious Diseases, vol. 10, pp. 374–379, 2006.
[23]
M. Gandhi and R. M. Greenblatt, “Hair it is: the long and short of monitoring antiretroviral treatment,” Annals of Internal Medicine, vol. 137, no. 8, pp. 696–697, 2002.
