Medicine/ 6. Experimental and clinical pharmacology

MD A.Kh.Rakhmanov, K.Z.Khakimov, U.S.Akbarov

Interuniversity Research Laboratory of the Tashkent Medical Academy, Republic of Uzbekistan

The effectiveness of the load test in determining the absorptive - excretory function of the liver with hepatodepression at the prepubertal period.

Viral hepatitis is an important clinical problem, both worldwide and in the CIS countries. Every year they are detect for the first time at one million people in the world and affect the most capable part of a society: the highest morbidity observed among individuals in the period to maturity and adulthood (15-30 years) [1,2,3].

Liver affection of different etiology accompanied with dysfunction of hepatocytes of varying intensity: from asymptomatic hepatodepressionto the development of hepatic encephalopathy and coma, the first meets quite frequently [1,4]. It should be noted that hepatodepression– rather functional syndrome, as permanent morphological signs defaulted and not always revealed necrosis of hepatocytes. Consequently, in essence hepatodepression- this suppression of detoxification and, partly, synthetic functions of organ [4].

It is known that there are number of drugs that are excreted in invariable condition by the liver composed of bile. The pharmacokinetic parameters of these drugs entirely depend on the absorptive - excretory functions of the liver [5].In this connection, these drugs are often used to evaluate the absorptive - excretory functions of the liver in various pathological conditions. One such drug is kardiogrin (KG) [6].

The aim of this work was to study absorptive - excretory function of the liver in its acute chlorinated carbon (CCl₄) affection in the prepubertal period (PP).

Material and methods of research.

Experiments were examined on 24 one month of age rabbits of both sexes of Chinchilla breed. Model of acute toxic hepatitis (ATH) reproduce by intragastricinjecting 50% oil solution of CCl₄ at a dose of 0.25 ml/kg once a day for 4 days, each experimental group consisted of 6 young rabbits. 1, 3 and 6 days later, after the last insertion of hepatotoxin, in animals detected absorptive - excretory function of the liver by chromo - diagnostic test using KG (USA) [7]. Studies carried out in the morning, a freshly prepared dye solution was injected into the jugular vein at a dose of 0,5 mg/kg body weight, and after 1, 3, 6, 15, 30 and 60 minutes its contents was determined by spectrophotometry in the plasma of blood. The concentration of the dye in the blood was foundedin the calibration curve,ready-built by using standard solutions of KG. Pharmacokinetic parameters of KG were computed by the two parts models with intravenous injection of the drug [8,9]. At the same time determined the circulation blood volume (CBV) and the hepatic blood velocity (Vn), which is calculated by the formula [10].

Where: Vn - the hepatic blood velocity (ml/min_*kg), t_½- half-life period, m - weight in kilograms. The experiments were donewithobservance of rules accepted by the European Convention for the Protection of Vertebrate Animals used for experimental and other scientific exports (ETS N 123 Strasbourg, 18.03.1986 year). The finding were statistically processed using the standard software package Statistic for Windows by commonly known methods of variation statistics with the valuation of the significance of the indicators and the differences of considered samples by Student t-test.

Results and discussion.

The finding results attest that the first day ATH, induced by injection of CCl₄, characterized by a significant prolongation of half-life (t_½α) on 107,7% and period of half-elimination (t_½β) on 269,1% of norm. The volume of drug disposition in the central (Vc) and peripheral (Vdss) cameras is also increased to 62,6% and 46,4%, respectively from normal ranges. This led increasing of distribution of dye in balanced state (Vp) on 60,1% from the values of the intact group. These changes are accompanied by rate reduction of KGtransition from blood to liver (K₁₂) on 43,7%, back into the blood from the liver (K₂₁) and from the liver to bile (K_el) on 57,3% and 69,5% respectively from normal ranges. All of these changes set conditions for nearly twofold increase in the area under the pharmacokinetic curve (AUC) and decreased plasma clearance (Cl_p) of the drug to 49,1% from norm. In a one day after stopping injection of CCl₄hepatic blood velocity (Vn) decreased to 29,3% from the norm.

As can be seen from table 1 on the third day of ATH all pharmacokinetic parameters of KG remained on the level indicators of the previous studies.

Table 1.

Pharmacokinetic options of cardiogrin in rabbits with acute toxic hepatitis in the prepubertal period.

Indicators	Research terms, days
	Intact	1	3	6
t1/2 min	1,43 ± 0,06	2,97 ± 0,08*	2,67 ± 0,17*	2,86 ± 0,30*
t1/2 min	29,15 ± 1,05	107,60 ± 7,06*	105,42 ± 8,58*	95,36 ± 6,42*
Vc, ml/kg	15,93 ± 0,88	25,91 ± 1,17*	21,35 ± 0,71*	24,01 ± 0,70*
Vdss, ml/kg	18,98 ± 1,08	30,36 ± 1,41*	24,49 ± 0,82*	28,56 ± 0,99*
Vp, ml/kg	3,04 ± 0,22	4,45 ± 0,36*	3,14 ± 0,17	4,59 ± 0,34*
K12, min^– 1	0,288 ± 0,014	0,162 ± 0,006*	0,185 ± 0,013*	0,170 ± 0,19*
K21, min^– 1	0,082 ± 0,005	0,035 ± 0,001*	0,035 ± 0,003*	0,041 ± 0,003*
Kel, min^– 1	0,145 ± 0,007	0,044 ± 0,003*	0,052 ±0,004*	0,046 ± 0,003*

Note: * - statistically significant differences compared with intact animals.

In a sixth day after stopping injection of CCl₄, 100% detected increasing of dye half-life t_½α, even so increasing of t_½βcome to 227,1% respectively from normal ranges. There was a rise in drug distribution volume Vcand Vdsson 50,7 and 50,9% respectively against the background of increasing its distribution in Vpon 50,6% compared to normal rates.

The performance of all three constants, i.e. the transition rate of the K₁₂, K₂₁ and K_eldrug, were reduced by 41,0%, 50,1% and 68,4% respectively from the norm.

Thus contrary AUC was increased to 110,0% and Cl_pKG decreased to 51,8% from the norm. Simultaneous detection of Vn showed its decrease to 26,6% from the normal rate.

Many studies have found that circulatory disorder of one or other organ [11], is one of the causes of hypoxia. This process entails the following changes in hepatocytes: increasing of the lipid peroxidation, inhibition of the enzymesactivity of antioxidantand monooxygenasesystems of cells [12,13]. Afterwards, the crippling of the hepatocytesmembranes leads to exiting to blood intracellular enzymes - transaminases and processing the syndrome of endotoxemia[13].

Thus, our studies have shown that the ATH reproduced by injection of CCl₄ in rabbits at prepubertal period, results to significant failures of absorptive - excretory function of hepatocytes and a significant reduction of the hepatic blood velocity. Identifying of failures persisted after the sixth day from the start of reproduction of the pathological process.

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