Зв'язок між фармакокінетикою рифампіцину і станом перекисного окислення ліпідів у хворих на туберкульоз

Abstract

Метою даної роботи було з’ясування можливого зв’язку між вмістом рифампіцину і маркерами стану про- та антиоксидантної систем у хворих на туберкульоз. Вміст рифампіцину, рівень дієнових кон’югатів (ДК) і активність каталази вимірювали у венозній крові через 2,4,6 і 24 год. після прийому стандартної дози препарату. Зразки крові були отримані у 84 хворих на легеневий туберкульоз, що вперше діагностовано, в Одеському обласному протитуберкульозному диспансері в 2012 р. Зменшення концентрації рифампіцину у хворих на туберкульоз асоціювалась зі зменшенням рівня дієнових кон’югатів і збільшенням активності каталази. Концентрація рифампіцину у хворих на туберкульоз через 6 год. після прийому препарату прямо корелювала з рівнем дієнових кон’югатів і обернено корелювала з активністю каталази. Період напіввиведення рифампіцину (4-6 год.) і AUC прямо корелювали з вмістом дієнових кон’югатів і обернено – з активністю каталази і антиоксидантним індексом.

It is well known that tuberculosis (TB) is associated with activation of oxidant system and inhibition of antioxidant systems. Successful treatment usually normalizes this imbalance. Among the courses of such imbalance in oxidant-antioxidant system the leading position ranks the tuberculosis intoxication by itself that provokes the systemic intoxication as well as the action of antituberculosis agents. The aim of this work was to investigate possible relation between pharmacokinetics rifampicin (R), the most effective antituberculosis antiobiotic, and the level of pro- and antioxidant system markers in TB patients. The study involved 84 patients with pulmonary TB which was first diagnosed at Odesa TB dispensary in 2012. There were 39 (46,4 %) females and 45 (53,6%) of mean age 35,9 years. All the patients were given the injections of rifampicin in a dose of 8-12 mg/kg of body wt daily. Rifampicin concentration was detected in venous blood taken from the patients in 2, 4, 6 and 24 hrs after introducing its standard doses (8-12 mg/kg/day) according to Chubaryan V.T., 1994. The drug was extracted by allying chloroform and KOH and then the drug concentration was measurement by spectrophotometer SP-46. The level of diene conjugates and catalase activity in blood serum were measured by heptane-isopropyl spirit and hydrogen peroxide with ammonia molibdate correspondently and following spectrophotometry. In addition we calculated antioxidant index as ratio of catalase activity to level of diene conjugates. Dropping of R concentration in TB patients may be associated with the decrease of diene conjugates level and increase of catalase activity. The maximal level of diene conjugates – 1.663 mol/l - was observed 2 hrs after R intake and the lowest level – 1,521 – in 24 hrs. Ccatalase was observed to demonstrate the opposite dynamics. Six hours after R ingestion a direct correlation was found between R concentration and diene conjugates level (estimated t-criteria 2,556, critical t-criteria hereinafter 1,998) on one hand and reverse correlation between R concentration and catalase activity (estimated t-criteria -1,991). In addition it was calculated starting and terminal half-life of R - Т1/2 (4-6 hrs) and Т1/2 (6-24 hrs) correspondently and AUC (area under the curve) of R. So, Т1/2 (4-6 год.) for R was 6,76±2,03 hrs; Т1/2 (6-24 hrs.) – 36,23±13,51 hrs; AUC – 245,63±51,64 mcg/ml*hrs. Daily average level of diene conjugates directly correlate with AUC of R (estimated t-criteria was 2,439) and Т1/2 (6-24 hrs) (estimated t-criteria was 2,424). The half-life of R (4-6 hrs) was in direct correlation with diene conjugates 4 and 6 hrs after R intake (estimated tcriteria were 2,426 and 4,191 correspondently). Daily average activity of catalase was in reverse correlation with AUC of R (estimated t-criteria was - 2,018) and Т1/2 (4-6 hrs) of R (estimated t-criteria was -2,905). Also catalase activity 2 hrs after R ingestion has been in reverse correlation with Т1/2 (4-6 hrs) - estimated t-criteria was -3,530. Antioxidant index has been in reverse correlation with diene conjugates level 6 and 24 hrs after R ingestion (estimated t-criteria were -2,605 and -3,210 correspondently). Т1/2 (4-6 hrs) of R also was in reverse correlation with antioxidant index. For example, estimated t-criteria 2 hrs after R intake was -4,650; 4 hrs after R intake -3,329; 24 hrs after -2,508. Thus, the obtained data have shown the direct correlation between R concentration in blood of TB patients and diene conjugates concentration, and the reverse correlation between R concentration and catalase activity, antioxidant index. The connection between R concentration and oxidant/antioxidant balance has been proved by revealing of direct correlation between AUC of R and diene conjugates on one hand and reverse correlation between AUC of R and catalase activity and antioxidant index on the other hand. Slow elimination of R (high T1/2 (4-6 hrs)) associate with high level of lipids peroxidation products and low activity of catalase. So, rifampicin contributes to oxidant/antioxidant imbalance during TB treatment.

Целью данной работы было исследование возможной связи между содержание рифампицина и маркерами состояния про- и антиоксидантной систем у больных туберкулезом. Содержание рифампицина, уровень диеновых конъюгатов (ДК) и активность каталазы измеряли в венозной крови через 2,4,6 и 24 час. после приема стандартной дозы препарата. Образцы крови были получены от 84 больных с впервые диагностированным туберкулезом легких в Одесском областном противотуберкулезном диспансере в 2012 г. Уменьшение концентрации рифампицина у больных туберкулезом ассоциировалось с уменьшением уровня диеновых конъюгатов и увеличением активности каталазы. Концентрация рифампицина у больных туберкулезом через 6 час. после приема препарата прямо коррелировала с уровнем диеновых конъюгатов и обратно коррелировала с активностью каталазы.