EXPERIMENTAL STUDIES
ЕКСПЕРИМЕНТАЛЬНІ ДОСЛІДЖЕННЯ
Bardachivska K.I., Gurina N.M., Shalamay A.S., Nikolayev V.G.
SORPTION ACTIVITY OF DETOXIFICATION DRUGS TOWARDS THE ESSENTIAL ANTITUBERCULOUS DRUGS
(ПОГЛИНАЛЬНА АКТИВНІСТЬ ЗАСОБІВ ДЕТОКСИКАЦІЇ ВІДНОСНО ДЕЯКИХ ОСНОВНИХ
ПРОТИТУБЕРКУЛЬОЗНИХ ПРЕПАРАТІВ)
Institute of experimental pathology, oncology and radiobiology named after R.E., Ukraine Academy of
Sciences
© Bardachivska K.I., Gurina N.M., Shalamay A.S., Nikolayev V.G., 2009
Tuberculosis pharmacotherapy and prophylaxis requires active simultaneous application of the most
effective and the safest therapies [1]. Modern tuberculosis therapy also provides complex use of specific
antibacterial drugs and medications of various pharmacological groups. Combined chemotherapy
principle allows to augment treatment efficiency as a whole. Nevertheless, it should be taken into
consideration that activity of antituberculous drugs is accompanied by side effects whose manifestation
can increase both in their combined use and in administration of concomitant drugs [2].
Acute and chronic hepatitis is one of the most widespread complications of antituberculous therapy in
the patients [3, 4]. An excess of serum ALT level three and more times compared with the norm is a
criterion of hepatotoxicity development. In patients receiving isoniazid and rifampicin without
pyrazinamide experience hepatic disorders seldom enough. Including of pyrazinamide in the treatment
schedule implied much higher risk of development of drug hepatitis [5, 6]. In its turn, use of isoniazid
can cause neurologic disorders, and, which is more, isoniazid-associated psychosis [7] and neuropathy,
especially with additional risk factors being present (HIV, alcoholism, diabetes, kidney insufficiency,
undernutrition etc.). Thus, for prophylaxis and treatment of neuropathies caused by isoniazid intake, a
necessity occurs to use its antidote, pyridoxine [8, 9].
Despite the essential progress in tuberculosis treatment, detoxification problem in long-term
andministration of antituberculous drugs remains relevant.
To reduce toxicity of antituberculous drugs as well as to eliminate complications, sorption methods are
used [10–13]. In patients with hepatic function disorders that cannot be corrected with hepatotropic
therapy, hemosorption on carbon sorbents allows to normalize blood biochemical values (bilirubin, AST,
ALT) and improve tolerability of antituberculous drugs in patients with toxicoallergic reactions to
antituberculous drugs [10]. Experiments on rats have shown that enterosorbent chitosan demonstrates
hepatoprotective activity against toxic action of isoniazid and rifampicin [11]. In oral administration of
carbon-mineral enterosorbent SUMS (СУМС) 1 in patients with pulmonary tuberculosis with toxic
hepatic disorder, liver metabolic activity has improved, drug intolerability has reduced as well as level of
primary and secondary products of lipid peroxide oxidation. At the same time, no changes of total
isoniazid clearance were observed in the area under curve on the background of enterosorption [12]. A
positive tendency has been detected for phytosorbent influence (fumed silicone dioxide with propolis)
on immunological values in patients with newly diagnosed pulmonary tuberculosis [13].
Objectives of this study included determination of total sorption activity of enterosorbents and dietary
fibers towards the essential antituberculous drugs — isoniazid, pyrazinamide and rifampicin — in in vitro
experiments.
Study materials and methods
Study objects included: carbon enterosorbent AUT (АУТ), organsilicone enterosorbent Enterosgel and
dietary fibers — microcrystal cellulose (MCC).
Due to study drugs having different chemical nature, for their comparison values of marker compounds
were found – vitamin B12 (marker of medium molecular weight, 1355 Da) and creatinine (low-molecular
marker, 133 Da). Sorption activity towards vitamin B12 for carbon sorbent AUT was 23.10 mg/g, for
Enterosgel — 3.85 mg/g, for MCC — 1.54 mg/g, towards creatinine — 19.00 mg/g, 0.86 mg/g and 0.30
mg/g, respectively.
To determine common sorption activity of the above said samples of enterosorbents and dietary fibers
towards antituberculosis drugs, the following substances were studied: isoniazid, pyrazinamide and
rifampicin.
Adsorption level of the substances was determined by the difference of their concentration before and
after the contact with enterosorbents and MCC in the static regimen. Contact time was two hours.
Sorption was performed in the media corresponding to gastric (рН 1.6) and pacnreatic juice (рН 6.8).
Drug substance concentration was measured by spectorfotometry at the following minute lengths:
isoniazid — λ=260 nm, pyrazinamide — λ =268 nm, rifampicin — λ =334 nm, corresponding to sorption
maximum of these substances.
Statistical data processing was conducted using Microsoft Excel programs: mean average (М) and rootmean-square error (m) was calculated.
Results and their discussion
As a result of the studies conducted in vitro, total sorption activity of carbon enterosorbent AUT,
organsilicone enterosorbent Enterosgel and MCC dietary fibers towards antituberculous drugs —
isoniazid, pyrazinamide and rifampicin.
In determination of activity of the substances studied towards the drugs, substance quantities were
calculated that approximately corresponded with nominal concentration of the drugs after their single
administration in the models of homogenous distribution within the GIT.
Data on isoniazid sorption by sorbents and dietary fibers from the media corresponding to acidity of
gastric (рН 1.6) and pancreatic (рН 6.8) juice are present in Table 1.
Table 1. Total activity of enterosorbents and dietary fibers towards isoniazid
No.
Substances studied
1
2
AUT
Enterosgel
Sorption in рН 1.6
mg/g
9,11 ± 0,410
0,02 ± 0,006
Sorption in рН 6.8
mg/g
9,59 ± 0,46
0,09 ± 0,01
3
MCC
0,01 ± 0,002
0,06 ± 0,01
Table 2. Total activity of enterosorbents and dietary fibers towards pyrozinamide
No.
Substances studied
1
2
3
AUT
Enterosgel
MCC
Sorption in рН 1.6
mg/g
9,91 ± 0,48
0,15 ± 0,02
0,11 ± 0,01
Sorption in рН 6.8
mg/g
9,88 ± 0,42
0,13 ± 0,01
0,09 ± 0,01
Table 3. Total activity of enterosorbents and dietary fibers towards rifampicin
No.
Substances studied
1
2
3
AUT
Enterosgel
MCC
Sorption in рН 1.6
mg/g
19,73 ± 0,72
1,50 ± 0,18
0,32 ± 0,02
Sorption in рН 6.8
mg/g
19,91 ± 0,71
1,13 ± 0,13
0,31 ± 0,02
As can be seen from Table 1, carbon enterosorbent AUT actively adsorbed isoniazid both in the acid
medium and the neutral one. Isoniazid sorption by Enterosgel and MCC in the acid medium was almost
absent. The most active adsorption was detected in the neutral medium in all the cases.
Pyrazinamide sorption by all the substances studied was the highest one for the acid medium. The
highest total sorption activity towards pyrazinamide was detected in enterosorbent AUT, while its
enterosorption by Enterosgel and MCC was only 1-1.5% (Table 2).
Data on rifampicin sorption by sorbents and dietary fibers are present in Table 3. Similar with the
previous cases, AUT has demonstrated high sorption activity towards rifampicin. In comparison with
carbon enterosorbents, Enterosgel adsorbed rifampicin 13-17 times less, however, these values were
significantly higher for the other studies of antituberculous drugs. Moreover, in the acid medium
Enterosgel was 1.3 times more active than in the neutral one. Rifampicin sorption by dietary fibers was
insignificant in both media.
Conclusions
Carbon enterosorbent AUT has demonstrated a significantly higher sorption activity towards
antituberculous drugs – isoniazid, pyrazinamide and rifampicin – in comparison with organosilicone
enterosorbent Enterosgel and MCC dietary fibers both in the medium corresponding to gastric acidity
and in that corresponding to pancreatic acidity.
Thus, in case of necessity, Enterosgel and MCC can be administered even with simultaneous intake of
antituberculous drugs, while carbon enterosorbents should be used strictly between administration of
these drugs or according to the schedule, in which antituberculous drugs are administered before or
during the meal and enterosorbent – 1.5-2 hours after.
The data obtained also testify that carbon enterosorbents can be used as a reliable way of
detioxification in overdosis of the studied antituberculosis drugs.
REFERENCES
1. Feschchenko Yu.I. et al. Assessment of significance of adverse reactions of antituberculous drugs in
tuberculosis treatment // Ukrainian Medical Journal - 2008. - Vol. 65, № 3 - P. 117–125.
2. Mashkovsky M.D. Medications. Vol. 1-2. Vol.2. Edition 14, updated. Moscow, "Издательство Novaya
Volna" - 2000.- 608 p.
3. Hussain, Z.Antituberculosis drug-nduced hepatitis: risk factors, prevention and management [Text] /
Z. Hussian, P. Kar, S. A. Hussain// Indian J. Exp. Biol. — 2003. — Vol. 41, № 6. — P. 1226–1232.
4. Wada, M. Antituberculosis drug-induced hepatitis [Text] / M. Wada // Kekkaku. — 2005. — Vol. 80,
№ 9. — P. 607–611.
5. Chang, K. C.Hepatotoxicity of pyrazinamide: cohort and case control analyses [Text] / K. C. Chang, C.
C. Leung, W. W. Yew, T. Y. Lau,C. M. Tam // Am. J. Respir. Crit. Care Med. — 2008. — Vol. 177,№ 12. —
P. 1391–1396.
6. Drug-induced hepatotoxicity caused by antituberculosis complicated with chronic hepatitis [Text] / Y.
Kaneko et al. //Kekkaku. — 2008. — Vol. 83, № 1. — P. 13–19.
7. Witkowski, A. E. Isoniazid-associated psychosis [Text] / A. E. Witkowski, C. G. Manabat, J. A. Bourgeois
// Gen. Hosp. Psychiatry. —2007. — Vol. 29, № 1. — P. 85–86.
8. Steichen, O.Isoniazid induced neuropathy: consider prevention [Text] / O. Steichen, L.
Martinez%Almoyna, T. De Broucher // Rev.Mal. Respir. — 2006. — Vol. 23, № 2. — P. 157–160.
9. Maw, G. Isoniazid overdose: a case series, literature review and survey of antidote availability [Text] /
G. Maw, P. Aitken // Clin. Drug Investig. — 2003. — Vol. 23, № 7. — P. 479–485.
10. Sorption detoxification in tuberculosis patients / Pidufala G.R. // Therapy. — 1991. — № 6. —P. 25–
28.
11. Santhosh, S.Hepatoprotective activity of chitosan against isoniazid and rifampicin-induced toxicity in
experimental rats [Text] /S. Santhosh, T. K. Sini, R. Anandan, P. T. Mathew // Eur. J.Pharmacol. — 2007.
— Vol. 572, № 1. — P. 69–73.
12. Influence of enterosorbent SUMS 1 on isoniazid pharmacokinetics an lipid peroxide oxidation in
tuberculosis patients with other drug-induced liver disorders / Kolpakova T.A. et al // Tuberculosis
problema. — 2001. — № 3. —P. 34–36.
13. Manohina O.Yu.Phytosorbent influence on immunologic values in patients with newly diagnosed
pulmonary tuberculosis with purulent caverns / Manohina O.Yu. // Ukt.pulmonol.journ. — 2006. — №
4. — P. 59–60.