BACKGROUND: Isoniazid(INH) and rifampicin(RFP) are potent antituberculous drugs which have made tuberculous disease become decreasing. In Korea, prescribed doses of INH and RFP have been different from those recommended by American Thoracic Society. In fact they were determined by clinical experience rather than by scientific basis. Even there has been. few reports about pharmacokintic parameters of INH and RFP in healthy Koreans. METHOD: Oral pharmacokinetics of INH were studied in 22 healthy native Koreans after administration of 300mg and 400mg of INH to each same person successively at least 2 weeks apart. After an overnight fast, subjects received medication and blood samples were drawn at scheduled times over a 24-hour period. Urine college lion was also done for 24 hours. Pharmacokinetics of RFP were studied in 20 subjects in a same fashion with 450mg and 600mg of RFP. Plasma and urinary concentrations of INH and RFP were determined by high-performance liquid chromatography(HPLC). RESULTS: Time to reach peak serum concentration (Tmax) of INH was 1.05α0.34 hrs at 300mg dose and 0.98α0.59 hrs at 400mg dose. Half-life was 2.49α0.88 hrs and 2.80α0.75 hrs, respectively. They were not different significantly(p>0.05) Peak serum concentration(Cmax) after administration of 400mg of INH was 7.14α 1.95mcg/mL which was significantly higher than Cmax (4.37α1.28mcg/mL) by 300mg of INH(p<0.01). Total clearance(CLtot) of INH at 300mg dose was 26.76α11.80mL/hr. At 400mg dose it was 21.09α8.31mL/hr which was significantly lower(p<0.01) than by 300mg dose. While renal clearance(CLr) was not different among two groups nonrenal clearance(CLnr) at 400mg dose (18.18α8.36mL/hr) was significantly lower than CLnr (23.71α11.52mL/hr) by 300mg dose(p<0.01). Tmax of RFP was 1.11α0.41 tut at 450mg dose and 1.15 α0.43 hrs at 600mg dose. Half-life was 4.20α0.73 hrs and 4.95α2.25 hrs, respectively. They were not different significantly(p>0.05). Cmax after administration of 600mg of RFP was 13.61 α3.43mcg/mL which was significantly higher than Cmax(10.12α2.25mcg/mL) by 450mg of RFP(p<0.01). CLtot of RFP at 450mg dose was 7.60α1.34mL/hr. At 600mg dose it was 7.05α 1.20mL/hr which was significantly lower(p<0.05) than by 450mg dose. While CLr was not different among two groups, CLnr at 600mg dose(5.36α1.20mL/hr) was significantly lower than CLnr(6.19α 1.56mL/hr) by 450mg dose(p<0.01). CONCLUSION: Considering Cmax and CLnr, 300mg, of INH and 450mg RFP might be sufficient doses for the treatment of tuberculosis in Koreans. But it remains to be clarified in the patients with tuberculosis.
Half-Life ; Humans ; Isoniazid* ; Korea ; Lions ; Pharmacokinetics ; Plasma ; Rifampin* ; Tuberculosis ; Volunteers*

BACKGROUND: Since up to 90% of a theophylline dose is biotransformed, probably by interaction with one or more the variants of the cytochrome P-450 drug metabolism system, anti-tuberculosis agents including drugs influencing microsomal enzyme systems, such as isoniazid and rifampicin, may be affect the elimination of theophylline. METHODS: The effect of combination therapy with isoniazid(INH), rifampicin(RFP), ethambutol(EMB) and pyrazinamide(PZA) on the pharmacokinetics of theophylline was evaluated by a computer program using Bayesian method. Three group were divided as follows. Group lis control, Group II is treated with INH, RFP, EMB and PZA and Group lll is treated with INH, RFP and EMB. All of them were non-smoker who were normal in liver and renal functions, and not administered drugs affecting on the clearance of theophylline with exception of anti-tuberculous agents. RESULTS: When it compared control with test groups, the clearance of theophylline in Group ll and Group lll was significantly decreased(p<0.001), and half life in Group ll and Group lll showed significant elevation(p<0.001). However there were no significant differences in clearance and half life between the Group ll and Group lll. CONCLUSION: These results suggest that theophylline dose may be need of readjustment in concurrent medica fion of anti-tuberculous agents including INH, RFP, and EMB.
Bayes Theorem ; Cytochrome P-450 Enzyme System ; Ethambutol* ; Half-Life ; Isoniazid* ; Liver ; Metabolism ; Pharmacokinetics* ; Pyrazinamide ; Rifampin* ; Theophylline*

BACKGROUND: Tuberculosis is more prevalent in dialysis patients than in the general population, and more difficult to make a diagnosis, and often leads to death, Moreover, extra-caution is needed in prescribing anti-tuberculosis medications as dose modification is frequently needed in patients with renal insufficiency. Several pharmacokinetic studies have been performed for antimycobacterial regimens in patients with renal insufficiency, including under hemodialysis. However, the anti-mycobacterial regimens of patients on peritoneal dialysis have been made based on empirical methods because of few pharmacokinetic studies. METHODS: To elucidate the pharmacokinetic profiles of anti-mycobacterial regimens for peritoneal dialysis, we measured both plasma and peritosol concentrations of anti- tuberculous drugs including isoniazide, rifampin and pyrazinamide in 9 patients maintained on chronic ambulatory peritoneal dialysis(CAPD). RESULTS: After a conventional oral dose of anti-tuberculosis medication, their plasma concentrations were in the therapeutic range, but the peritosol concentration of rifampin was below the therapeutic range. CONCLUSION: No dose adjustments are required for isoniazid, rifampin and pyrazinamide for the treatment of systemic or peritoneal tuberculosis in CAPD patients. On the contrary, oral rifampin is not expected to be effective in the treatment of tuberculous peritonitis, because of its low peritosol concentration.
Diagnosis ; Dialysis ; Humans ; Isoniazid ; Peritoneal Dialysis* ; Peritoneal Dialysis, Continuous Ambulatory ; Peritonitis, Tuberculous ; Pharmacokinetics* ; Plasma ; Pyrazinamide ; Renal Dialysis ; Renal Insufficiency ; Rifampin ; Tuberculosis

OBJECTIVETo establish a high-performance liquid chromatography (HPLC)-based method for determining isoniazide concentration in pleural effusion and plasma of patients with tuberculous pleurisy, and evaluate the permeability of isoniazide from blood into pleural effusion.

METHODSWe collected pleural effusion from 15 patients with tuberculous pleurisy 2 h after administration 300 mg isoniazide in the morning of day 1. Pleural effusion and plasma were obtained 2 h after isoniazide administration on day 3. Isoniazide concentration was measured using HPLC, and the penetration rate of isoniazide in pleural effusion was calculated.

RESULTSIsoniazide concentration in the pleural effusion averaged 1.156∓1.190 µg/ml in the 15 patients at 2 h after isoniazide administration on day 1. On day 3, isoniazide concentration was 1.920∓1.294 µg/ml in the pleural effusion and 2.445∓1.463 µg/ml in the plasma, and the mean penetration rate of isoniazide from blood into the pleural effusion was 86.0%.

CONCLUSIONAs isoniazide has a high penetration rate into the pleural effusion in most patients, continuous oral administration of isoniazid has been sufficient to achieve an effective treatment concentration, and intrapleural injection of isoniazide may seem unnecessary for non-drug-resistant tuberculosis pleurisy.

Adolescent ; Adult ; Aged ; Chromatography, High Pressure Liquid ; methods ; Female ; Humans ; Isoniazid ; pharmacokinetics ; Male ; Middle Aged ; Permeability ; Pleura ; metabolism ; Pleural Effusion ; metabolism ; Tuberculosis, Pleural ; metabolism ; Young Adult

OBJECTIVETo study the distribution of isoniazid and its metabolite in spinal tuberculosis following chemotherapy.

METHODSTwenty-three patients with spinal tuberculosis received chemotherapy with 2SHRZ/16HRZ (for a total of 18 months). Four weeks after the chemotherapy, all the patients underwent surgery and specimens of the serum, ilium and vertebral tissue including the sclerotic wall, focus inside the sclerotic wall (if present) and destructed foci were obtained. CT was performed in all the cases to test the HU of the foci before operation, and the levels of isoniazid and its metabolite in the specimen were measured with high-performance liquid chromatography (HPLC).

RESULTSThe levels of isoniazid and its metabolite were the highest in the serum, followed by normal ilium and non-sclerotic bone, and were extremely low in the sclerotic wall and foci. Their levels in the non-sclerotic bone of the compromised vertebra and normal vertebra showed no significant difference (P>0.05), but in the sclerotic bone, their levels were significantly higher than in the normal vertebra (P<0.05). Isoniazid and its metabolite are hardly detectable in the sclerotic foci in the compromised vertebrae.

CONCLUSIONIsoniazid and its metabolite may reach therapeutic concentration in normal vertebra and nonsclerotic bones of the compromised vertebra, but not in the disease foci or the sclerotic bone of the compromised vertebrae.

Adult ; Aged ; Antitubercular Agents ; blood ; pharmacokinetics ; therapeutic use ; Chromatography, High Pressure Liquid ; Female ; Humans ; Isoniazid ; analogs & derivatives ; blood ; pharmacokinetics ; therapeutic use ; Lumbar Vertebrae ; metabolism ; Male ; Middle Aged ; Tuberculosis, Spinal ; drug therapy ; Young Adult

CYP1A2, CYP2D6 and N-acetyltransferase activities were estimated in 100 patients with bladder cancer and 84 control subjects from measurements of theophylline, metoprolol and isoniazid and their metabolites in urine, respectively. The frequency of occurrence of slow acetylators of isoniazid and poor metabolizers of metoprolol were 16.7% and 1.2% in the control group and 16.3% and 2.0% in the cancer patient group. These differences were not significant. The recovery ratio of 1-methyluric acid(1-MU) from theophylline was significantly higher in patients with bladder cancer than in control subjects(0.340 +/- 0.016 versus 0.260 +/- 0.020, p< 0.05). The 1-MU recovery ratio was a significant, independent risk factor among the metabolic capacities tested as shown by logistic regression analysis, controlling for N-acetylation of isoniazid, hydroxylation of metoprolol, age, sex, and smoking. We concluded that the capacity for 3-demethylation of theophylline, as a reflection of CYP1A2 activity, is significantly associated with increased risk of nonoccupational urinary bladder cancer.
Acetylation ; Adult ; Aged ; Amines/metabolism ; Bladder Neoplasms/enzymology/*epidemiology ; Carcinoma, Transitional Cell/enzymology/*epidemiology ; Case-Control Studies ; Cytochrome P-450 CYP1A2 ; Cytochrome P-450 CYP2D6 ; Cytochrome P-450 Enzyme System/metabolism/*urine ; Disease Susceptibility ; Enzyme Induction ; Female ; Human ; Isoniazid/*pharmacokinetics ; Korea/epidemiology ; Logistic Models ; Male ; Methylation ; Metoprolol/*pharmacokinetics ; Middle Age ; Mixed Function Oxygenases/metabolism ; Mixed Function Oxygenases/metabolism ; Oxidoreductases/*urine ; Smoking ; Support, Non-U.S. Gov't ; Theophylline/*pharmacokinetics ; Uric Acid/analogs & derivatives/urine