EurJ Clin Pharmacol (1991) 41:35%361
be @eqerleg @Springer-Verlag 1991
Antipyrine kinetics in undernourished diabetics J. C. Shobha 1, I". C. Raghuram 2, A. Deva Kumar 1, and K. Krishnaswamf ~ Department of Pharmacology Gandhi Medical College and 2 National Institute of Nutrition Indian Council of Medical Research Jamai-Osmania, Hyderabad, India
Received: Aplil 3, 1990/Accepted in revised form: January 28, 1991
Summary. In developing countries diabetics frequently suffer from varying grades of malnutrition. The combined effect of malnutrition and non-insuhn dependent diabetes ( N I D D M ) on the drug metabolising enzyme system has been evaluated using antipyrine as a protodrug. All the patients were under treatment and their plasma glucose values were within normal limits. The A U C of antipyrine was similar in all the groups. Although none of the kinetic parameters was altered in normal diabetics, the clearance of antipyrine was decreased and its half life was prolonged, with an increase in volume of distribution, in undernourished diabetics compared to undernourished controls. The results indicate that diabetes p e r se m a y not influence antipyrine kinetics when the blood glucose is well under control, but in the presence of undernutrition, it significantly alters the disposition of the drug.
Key words: Diabetes, Antipyrine; undernutrition, drug metabolism, pharmacokinetics
Diabetes mellitus is a c o m m o n metabolic disorder affecting 1-2 % of Indian population [1]. Diabetics depend on drugs either to control the hyperglycaemia or the associated long term complications throughout their life. It is known that the pharmacological responses to drugs depends on their blood concentrations, which in turn depend on drug metabolising enzyme systems [2]. Thus, it is important to know whether the liver microsomal enzyme system in diabetics is induced or inhibited. The current limited information available on drug metabolism in diabetics is equivocal [3, 4, 5]. Several factors, such as the type of diabetes [5], state of hyperglycaemia [6] and nature of drug studied [3] have all been shown to influence drug metabolism in diabetics. In addition to disease states, the nutritional status of an individual is one of the important environmental factors which is known to influence drug metabolism [7]. Although obesity has been shown to be a predisposing factor
in diabetes, epidemiological surveys in India indicate that the undernourished are equally susceptible to diabetes [8]. Recently, W H O even classified malnutrition-related diabetes as a separate disease category [1]. Although metabolism of several drugs has been separately evaluated in diabetics and undernourished subjects, so far there has b e e n no systematic study of the concomitant effect of protein energy malnutrition and diabetes on drug metabolizing enzyme system. In the present study, using antipyrine as a protodrug, the liver microsomal enzyme system has been evaluated in a group of normals and diabetics with and without malnutrition. The study was approved by the Ethical Committee of the Institute.
Subjects and methods Twelve male NIDDM patients aged 32 to 53 y (47.2 (2.6) y, mean with (SEM) participated in the study. The diagnosis of diabetes was based on the criteria laid down by WHO [1]. All the patients were on the antidiabetic drug glibenctamide (5-10 mg/day). Twelve apparently normal male subjects were included in the study as controls. Based on serum albumin level, both normals and diabetic patients were classified as wellnourished (> 3.5 g/dl) or undernourished ( < 3.5 g/dl). All the subjects were non-smokers and were free from liver and kidney disease as assessed by the serum transaminases, y-GT and creatinine levels. The pharmacokinetics of antipyrine was studied in all the diabetic patients and control subjects. Antipyrine 18 rag. kg-~ body weight was administered orally with 250 ml water after over night fasting. Food was not permitted for the next 2 h to ensure complete absorption. Blood samples were collected 2, 4, 6, 8 and 24 h after administration of the drug. Plasma antipyrine concentrations were determined by HPLC [9]. Half life (tje) and elimination rate constant (k) of antipyrine were calculated by the least squares method. The AUC was computed using the trapezoidal rule. The apparent volume of distribution (Vz) and clearance (CL) were calculated using standard formulae. Volume of distribution and clearance were expressed per kg body weight as there were significant differences in the body weight of subjects in the different groups.
360
J.C. Shobha and T. C. Raghuram: Antipyrine kinetics and diabetes
Table 1. Anthropometric data, serum albumin and fasting and post prandial plasma glucose levels (Mean with (SEM) Group
No.
1 WN Controls 2 WN Diabetics 3 UN Controls 4 UN Diabetics Level of significance
6 6 6 6
Weight (kg)
Body mass Index
Serum albumin (g/dl)
60.9 (1.9)" 22.0 (0.7)°' d 4.3 (0.3)a,c 70.1 (4.1) b'c 25.8 (1.0) b' d,e 4.3 (0.2) b' d 46.9 (3.0)a'c.d 17.7 (1.0) a' b,c 2.8 (0.1)c,d 54.6 (3.7)b'd 21.0 (1.3)¢'e 2.8 (0.3)a,b a, c = P < 0.001 a, b, c = P < 0.001 a, b = P < 0.01 b = P < 0.02 d, e = P< 0.02 c, d = P< 0.001 d=P
be @eqerleg @Springer-Verlag 1991
Antipyrine kinetics in undernourished diabetics J. C. Shobha 1, I". C. Raghuram 2, A. Deva Kumar 1, and K. Krishnaswamf ~ Department of Pharmacology Gandhi Medical College and 2 National Institute of Nutrition Indian Council of Medical Research Jamai-Osmania, Hyderabad, India
Received: Aplil 3, 1990/Accepted in revised form: January 28, 1991
Summary. In developing countries diabetics frequently suffer from varying grades of malnutrition. The combined effect of malnutrition and non-insuhn dependent diabetes ( N I D D M ) on the drug metabolising enzyme system has been evaluated using antipyrine as a protodrug. All the patients were under treatment and their plasma glucose values were within normal limits. The A U C of antipyrine was similar in all the groups. Although none of the kinetic parameters was altered in normal diabetics, the clearance of antipyrine was decreased and its half life was prolonged, with an increase in volume of distribution, in undernourished diabetics compared to undernourished controls. The results indicate that diabetes p e r se m a y not influence antipyrine kinetics when the blood glucose is well under control, but in the presence of undernutrition, it significantly alters the disposition of the drug.
Key words: Diabetes, Antipyrine; undernutrition, drug metabolism, pharmacokinetics
Diabetes mellitus is a c o m m o n metabolic disorder affecting 1-2 % of Indian population [1]. Diabetics depend on drugs either to control the hyperglycaemia or the associated long term complications throughout their life. It is known that the pharmacological responses to drugs depends on their blood concentrations, which in turn depend on drug metabolising enzyme systems [2]. Thus, it is important to know whether the liver microsomal enzyme system in diabetics is induced or inhibited. The current limited information available on drug metabolism in diabetics is equivocal [3, 4, 5]. Several factors, such as the type of diabetes [5], state of hyperglycaemia [6] and nature of drug studied [3] have all been shown to influence drug metabolism in diabetics. In addition to disease states, the nutritional status of an individual is one of the important environmental factors which is known to influence drug metabolism [7]. Although obesity has been shown to be a predisposing factor
in diabetes, epidemiological surveys in India indicate that the undernourished are equally susceptible to diabetes [8]. Recently, W H O even classified malnutrition-related diabetes as a separate disease category [1]. Although metabolism of several drugs has been separately evaluated in diabetics and undernourished subjects, so far there has b e e n no systematic study of the concomitant effect of protein energy malnutrition and diabetes on drug metabolizing enzyme system. In the present study, using antipyrine as a protodrug, the liver microsomal enzyme system has been evaluated in a group of normals and diabetics with and without malnutrition. The study was approved by the Ethical Committee of the Institute.
Subjects and methods Twelve male NIDDM patients aged 32 to 53 y (47.2 (2.6) y, mean with (SEM) participated in the study. The diagnosis of diabetes was based on the criteria laid down by WHO [1]. All the patients were on the antidiabetic drug glibenctamide (5-10 mg/day). Twelve apparently normal male subjects were included in the study as controls. Based on serum albumin level, both normals and diabetic patients were classified as wellnourished (> 3.5 g/dl) or undernourished ( < 3.5 g/dl). All the subjects were non-smokers and were free from liver and kidney disease as assessed by the serum transaminases, y-GT and creatinine levels. The pharmacokinetics of antipyrine was studied in all the diabetic patients and control subjects. Antipyrine 18 rag. kg-~ body weight was administered orally with 250 ml water after over night fasting. Food was not permitted for the next 2 h to ensure complete absorption. Blood samples were collected 2, 4, 6, 8 and 24 h after administration of the drug. Plasma antipyrine concentrations were determined by HPLC [9]. Half life (tje) and elimination rate constant (k) of antipyrine were calculated by the least squares method. The AUC was computed using the trapezoidal rule. The apparent volume of distribution (Vz) and clearance (CL) were calculated using standard formulae. Volume of distribution and clearance were expressed per kg body weight as there were significant differences in the body weight of subjects in the different groups.
360
J.C. Shobha and T. C. Raghuram: Antipyrine kinetics and diabetes
Table 1. Anthropometric data, serum albumin and fasting and post prandial plasma glucose levels (Mean with (SEM) Group
No.
1 WN Controls 2 WN Diabetics 3 UN Controls 4 UN Diabetics Level of significance
6 6 6 6
Weight (kg)
Body mass Index
Serum albumin (g/dl)
60.9 (1.9)" 22.0 (0.7)°' d 4.3 (0.3)a,c 70.1 (4.1) b'c 25.8 (1.0) b' d,e 4.3 (0.2) b' d 46.9 (3.0)a'c.d 17.7 (1.0) a' b,c 2.8 (0.1)c,d 54.6 (3.7)b'd 21.0 (1.3)¢'e 2.8 (0.3)a,b a, c = P < 0.001 a, b, c = P < 0.001 a, b = P < 0.01 b = P < 0.02 d, e = P< 0.02 c, d = P< 0.001 d=P
