Mohammad Saleem ( Quaid-e-Azam University, National Institute of Health, Islamabad. )
S.A. Malik ( Quaid-e-Azam University, National Institute of Health, Islamabad. )
Maqsood Ahmed ( Nutrition Division, National Institute of Health, Islamabad. )
Najeeba Saleem ( Nutrition Division, National Institute of Health, Islamabad. )
Phenotypes of slow and fast acetylators of isoniazid (INH) were determined in 157 subjects (80 normals and 77 patients with tuberculosis) from the twin cities of Rawalpindi and Islamabad. Plasma INH concentrations were determined chemically six hours after the drug ingestion. The findings indicate that 31.8% subjects were fast acetylators of the drug (JPMA 39: 285, 1989).
Studies have shown that a number of drugs including INH are acetylated and inactivated in the liver by the acetyl- transferase enzymes1. The rate of inactivation of INH varies in different individuals and in different races and is found to be genetically controlled2. It is well established that in the treatment of tuberculosis slow acety-lators of INTL are more prone to the untoward effects of the thug. The frequency of hepatic disorders on the other hand is connected with the fast acetylation of INTL. The greater hepatotoxicityby fast acetylators appears to result from the synthesis of acetylisoniazid which is further metabolized to acetyihydrazide which is extremely hepatotoxic3. Thberculosis is not a rare disease among Pakistanis and a considerable number of patients are taking INK. For all the above reasons, the present study was undertaken to determine the extent of fast and slow acetylators of INH.
PATIENTS AND METHODS
Subjects included 80 apparently healthy males from the National Institute of Health, Islamabad, weighing 50-70 Kgs, whose ages ranged from 20-60 years and 77 male tubercular patients from the Thberculosis Centre, Rawalpindi weighing 40-50 Kgs whose ages ranged from 17-60 years. The patients had proven infection with tubercle bacillus. After taking informed consent, the medications of the patients were stopped for 48 hours prior to the entry into the trial. The subjects were given INH orally in a single dose of 10 mg/Kg body weight (Isonex containing 100 mg INH, Pfizer Lab. Pak. Ltd.). Blood sample was collected in a stoppered tube containing EDTA six hours after the ingestion of the drug. The plasma was separated immediately and stored at -20°C until INH was determined. INH was determined spectrophotometrically by the method of Braun et al4 using ammonium vandatc, measurement of absorbance followed immediately at a wavelength of 430 nm. Calibration graphs were made on INH and used to determine IN}I concentration in the plasma. Back ground absorbance of plasma and recovery of INTL was also determined, so as to check the reliability of estimation.
The drug free background of human plasma in the method used is sufficiently low to cause any appreciable interference. Ninety five percent recovery of INH, when the drug was added to drug free plasma, further confirms the reliability of the method employed. The present data demonstrates that 31.8% subjects are fast acetylators. There was no significant difference in normal population and subjects suffering from tuberculosis. Similar results have been reported by Sharma et al who reported 39% subjects as fast acetylators of INH5. The highest percentage of fast acetylators (91%) is found in Japanese population6, while of Thai population are fast acetylators7. The distribution of fast acetylators in Negro and Caucasian population is about 50 percent6. The speed of inactivation of isoniazid has no practical effect on the response, if the drug is used dailyor2to 3 times a week, it has a marked influence on the frequency of neurotoxicity, i.e. peripheral neuropathy is lower in fast inactivators. It may be desirable to determine whether a patient is fast or slow acetylator if once a week regimen is contemplated.
The authors acknowledge the excellent cooperation extended by Dr. M. Husain, M.S., Tuberculosis Centre, Rawalpindi for providing the patients for this study.
1. Eidus, L.,Ling, G.M. and Harnanansingh, A.M.T. Isoniazid Excretion in fast and slow inactivation and its practical aspect for phonotyping. Arzreim - Forsch (Drugh Res.). Jahragang, 1971; II: 1699.
2. Tunkyi, and Smith, E.S. Isoniazid inactivation in Burmese subjects, Union of Burma, Life Sci., 1970; 30:147.
3. Giannopoulos, Z., Dozi-Vassiliades, J. and Granitsas, A. Phenotyping of isoniazid inactivators in Greeks. Folia. Bioch, et Biol Graeca., 1979; 16:91.
4. Braun, R., Jakel, H.P. and Schoneich, J. Genetic effects of isoniazid and the relationship to in vivo and in vitro biotransformation. Mutat. Res., 1984; 137:61.
5. Sharma, G.R. et. al. Classification of subjects as slowand rapid inactivators of isoniazid based on the ratio of acetylisoniazid to isoniazid in urine determined by a simple colorimeter method. IndianJ.Med. Res., 1976; 64:1456.
6. Dufour, A.P., Knight, R.A. and Harris, H.W. Genetics of isohiazid metabolism in Caucasian, Negro and Japanese population. Science, 1964; 145:391.
7. Sunahara, SM., Hrano and M. Ogawa. Genetic and geographic studies on isoniazid in activation. Science, 1961;134:1530.