Pharmacokinetic study of frusemide in healthy and cirrhotic indian subjects

Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work Pharmacokinetic Study of Frusemide in Healthy and Cirrhotic Indian Lecturer, Department of Health Sciences, University of Mauritius, Mauritius (Received 12 August 2007 and accepted 27 August 2007) ABSTRACT: Liver cirrhosis is associated with various complications such as ascites and fluid retention, progressing to development of hepatorenal syndrome, further compromising fluid elimination. Frusemide, a loop diuretic is normally administered to relieve fluid retentions. The kinetics of frusemide has not been conclusively reported in the three types of cirrhosis and among Indian subjects. The aim of the current study was to evaluate the kinetics of frusemide among healthy and Child’s A, B and C cirrhosis and compare with earlier data. 24 cirrhotic were selected and classified according to the Child’s-Pugh classification. 12 healthy male volunteers were screened and included in the study. 40 mg of frusemide was administered orally to both groups and blood samples were withdrawn at various intervals of time for a duration of 8 hrs. The amount of frusemide present in plasma was analyzed using HPLC. The volumes of distribution (Vd), area under curve (AUC), systemic clearance (CL), maximum concentration (Cmax), time for maximum concentration (tmax) in healthy volunteers were respectively 4.56 ± 0.15 L, 2258 ± 530.7, 4.97 ± 1.67 L/h, 892 ± 49.4 ng/ml, 85.20± 7.49 mins. Corresponding values in Group A were 5.00 ± 0.31 L, 2471 ± 228.6, 6.60 ± 2.90L/h, 1021 ± 47.97 ng/ml and 88.25 V 2.12 mins; in Group B 7.73 ± 1.10 L, 4038 ± 154.7, 8.84 ± 0.45 L/h, 1448 ± 43.20 ng/ml and 120 ± 1.89 mins; In group C cirrhosis 9.69 ± 1.32 L, 4085 ± 131.75, 3.49 ± 1.40 L/h, 1551± 59.02 ng/ml and 185.7 ± 2.68 mins respectively. Significant differences at 1% and 5% were observed among the cirrhotic groups and between healthy v/s cirrhotic patients. Data from current study do not correlate with earlier reports, carried mainly in Western population, due to possibly differences in instrumentation, etc but a possible genetic interplay should not be ruled out. Data from cirrhotic patients could not be effectively compared with earlier studies as kinetics of frusemide has not been conclusively been reported in the three categories of cirrhosis. KEY WORDS: Pharmacokinetic, Frusemide, Liver cirrhosis. Liver cirrhosis is one among the leading causes Pathological conditions such as biliary atresia, of death in the world and continues to represent a cystic fibrosis, gallstones, may also account for cirrhosis in certain conditions. Cirrhosis can be estimated to have caused around 25,000 deaths classified in three categories, according to the in the United States in 19972. The etiologies of Child’s- Pugh classification, depending on the liver cirrhosis are various and among them are drug induced cirrhosis or cirrhosis due to certain Corresponding Author: Dr. Yuvrajsing Dhunnoo, Email: [email protected] Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work Liver cirrhosis is accompanied by a host of generated kinetic data with earlier reported syndrome, causing retention of sodium and free water, decrease in renal perfusion and GFR3, thereby leading to edematic, and ascitic Patient recruitment: The study population Frusemide, a loop diuretic acting on the included 24 cirrhotic patients. The cause and Na+/K+/2Cl- symport in the luminal membrane diagnosis of cirrhosis was identified based on of the ascending loop of Henle, inhibits the clinical, biochemical and histological findings. chloride and sodium reabsorption, but has no effect on the distal nephron4. It has been assessment including serum albumin, BMI, and routinely used for the long term treatment of Child’s Pugh’s Classification were determined. ascites in cirrhotic patients. Frusemide is an Recruited patients did not have any other organic acid which is 96-98% plasma bound diagnosed disease and no history of fresh thereby limiting its delivery to the site of action. internal bleeding. Prior to start of the study, Pre-systemic metabolism of frusemide is carried patients were asked to stop frusemide intake 48 out by the intestine while systemic clearance of frusemide is mainly performed by the kidneys Volunteer Recruitment: 12 male volunteers in with contributions from the intestine and the the age group of 24-29 years were recruited. liver5. Since 30-50% of filtered sodium is Health status was ascertained by carrying out reabsorbed in the loop of Henle using this various biochemical tests, immunological tests transport system, frusemide has high natriuretic properties. At high dosage it may also increase Collection of Study sample: Prior to start of the study, all subjects were fasted overnight but Presence of edema, due to renal malfunctioning, water intake was allowed. The cirrhotic and the in cirrhosis, increases volume of distribution, healthy volunteers, all had 40 mg of oral frusemide and blood samples were collected in proteinuria, higher dosage of frusemide is heparinised tubes at specified time intervals following drug administration, up to six hours. concentrations given that urinary albumin binds Blood samples were centrifuged at 4000 rpm for frusemide and reduces its effectiveness. Clinical 5 mins, the supernatant withdrawn and stored in non-responders tend to have a decreased fraction Eppendorf tubes at -20°C till the analysis. of loop diuretics excreted in urine, thereby Reagents: Frusemide (99.9%) purity was kindly predisposing them to the side effects of Acetonitrile (HPLC grade) and Methanol (HPLC significantly metabolized by liver may lead to grade) were purchased from s.d fine chemical ltd severe side effects such as hyperuricaemia, India. Milli Q water was obtained from Millipore electrolyte disturbances such as hypokalaemia water systems, at a filter size of 0.22 mm. All and the hepatorenal syndrome observed in solutions were degassed under vacuum before cirrhotic patients6. Furthermore, genetic traits, use. Glacial acetic acid (HPLC grade), HCl and inter population variations and environmental NaOH pellets, were all brand products of Merck factors may also significantly contribute to Ltd. The mobile phase consisted of a mixture of variability in drug response and disposition, thereby leading to a major clinical problem7,8. prepared by mixing ACN and degassed milli-q Kinetics of frusemide have been earlier reported water in a ratio of 25:75. PH was adjusted to 5.0 in both compensated and decompensated cases of liver cirrhosis, but reported studies were mainly carried out in Western population, using either intravenous frusemide or at a dose of 80- consisted of a 515 Waters (USA) pump and UV 120 mg orally. However, no studies have been detector. The column was a 30 cm ´ 3.9 mm m reported on the kinetics of 40 mg oral frusemide Bondapack C18 reversed phase column, particle size 10 mM (Waters Assoc). The whole system The current study has been carried out among was controlled by a Millenium Version 2000 healthy and cirrhotic Indian subjects, with the Unix computer programming system. The flow aim to assess the pharmacokinetic parameters of rate was adjusted at 2.0 ml/min at an ambient Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work temperature. The detection was followed by using a simple UV lamp detector calibrated at 280 nm. The pressure varied between 1812-2012 Systemic clearance (Cls) was determined by: psi. Retention times were 5.0 mins and total run Pharmacokinetic Parameters: Concentration time curves of frusemide in plasma were drawn, extrapolated. The area under curve (AUC) was concentration of frusemide present in plasma, Value of (elimination constant) was calculated was 2258 ± 530.7 ng/ml hr. In groups A, B and from the elimination phase of the concentration C cirrhosis, corresponding values were 2471 ± time curve, using the following equation: 228.65, 4038 ± 154.7 and 4085 ± 131.75 ng/ml The difference in AUC between volunteers and group A patients was not statistically significant. volunteers and groups B and C patients was Significant differences were also observed in Volume of distribution (Vd) was calculated using AUC for groups B and C vis a vis group A (p<0.01). No statistical difference in AUC was observed between groups B and C of patients. Figure 1: Figure representing the areas under the curves attained in Healthy individuals and cirrhotic patients. Area under the curve is representative of the concentration of the drug in plasma, calculated using the trapezoidal rule. 1: Healthy Volunteers; 2: Group A Patients; 3: Group B Patients; 4: Group C Patients. Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work Volume of distribution (Vd): Mean volume of distribution (Vd) in volunteers and group A, B Frusemide (Cmax): Maximum plasma frusemide and C cirrhosis were respectively 4.56 ± 0.15 L, concentration attainable in healthy volunteers 5.00 ± 0.31 L, 7.73 ± 1.10 L and 9.69 ± 1.32 L. was calculated at 892 ± 49.4 ng/ml, whereas in There was no statistical difference between the various categories of Childs classification, healthy volunteers and group A patients. they were respectively 1021 ± 47.97, 1448 ± However, statistical significance was observed significant difference was observed between cirrhosis (p<0.01). Significant differences were healthy subjects and A group of cirrhosis, B and C groups of cirrhosis demonstrated significant cirrhotics at 5% (p<0.05). No significant difference in Cmax values vis a vis volunteers differences were observed between groups B and Systemic clearance (CLs): In healthy subjects Concentration (tmax): tmax values in healthy systemic clearance (CLs) was calculated to be volunteers and in groups A, B and C of cirrhosis 4.97 ± 1.67 l/h, and 6.60 ± 2.90, 8.84 ± 0.45, and were as follows: 85.20 ± 7.49, 88.25 ± 2.12, 120 3.49 ± 1.40 l/h respectively in Child’s A, B and ± 1.89 and 185.7 ± 2.68 minutes respectively. C cirrhosis. Clearance increased significantly Group A and volunteers displayed no significant among cirrhotics in comparison to volunteers difference in t max values, however, significant (p<0.05). However in C group of cirrhosis, differences at 1% were observed between B and systemic clearance decreased considerably. Figure 2: Relative volume of distribution of frusemide in volunteers and different categories of cirrhosis. Volume of distribution calculated gives an indication of rate of cirrhosis. 1: Healthy Volunteers; 2: Group A cirrhosis; 3 Group B cirrhosis; 4: Group C cirrhosis. Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work Figure 3: Systemic clearance was calculated using the formula, Clearance indicative of the liver functions. Significant differences was observed between healthy individuals and Group B and C cirrhotic patients Figure 4: Maximum plasma concentration of frusemide was calculated using the formula mentioned. Significant difference at 5% was observed between healthy individuals and cirrhotic patients. An inter-group difference among cirrhotic patients was also observed. Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work Figure 5: tmax values have been calculated using the formula. tmax values were significantly different between the healthy individuals and the different classes of cirrhotic patients. Current calculated Cmax value (0.904 ± 0.452 Liver cirrhosis highly influences the dynamic ng/ml) in healthy volunteers was lower than state of the human body. Earlier reports have earlier reported values11, which could be suggested altered kinetics of a spectrum of drugs explained to the difference in administered dose such as fluconazole9, omeprazole10 and a host of of frusemide (40 mg v /s 80 mg). Bioequivalence other drugs, which are generally administered during cirrhosis. Several kinetic studies in formulations used13. Correspondingly, mean area cirrhosis have been conducted, but there has under curve (2.23 ± 0.5 µg/ml h) were lower been no conclusive study on the three types of among Indian volunteers in view of the lower cirrhosis and also kinetic studies among Indian Cmax and tmax values. The mean half-life values population. The objectives of this study was to reported are divided on this issue. Higher mean shed light on the kinetics of frusemide among half- life values have been reported elsewhere, healthy and three types of cirrhosis among Indian but studies conducted by Rupp et al14 and population and evaluate any possible deviations Cutler et al15 have reported similar values as observed in our study. Age16, study design17, analytical methods and drug formulation18 may volunteers was not in accordance to previously also alter the course of the drugs in the body, reported data generated from healthy individuals. thereby explaining the difference in the observed Earlier reported tmax values ranged between 60- 70 mins11 and 100-150 mins after 40 mg and 80 Among the cirrhotic groups, observed kinetic mg of oral frusemide respectively in healthy parameters were not in accordance to earlier volunteers. In the current study, the tmax value reported values. The Cmax and tmax in our study among Indian volunteers was observed to be 90 increased proportionally in categories A, B and mins. The volunteers had fasted overnight, but C of cirrhosis vis a vis healthy volunteers. The some had breakfast after drug administration. increase in tmax is due to presence of edema of the gut along with changed motility, which is frusemide12, this might have possibly led to predominant in cirrhosis19. It is also reported that observed increase in tmax value. However, the cirrhosis causes prolongation of gastric emptying increase in tmax could also be due to slow time (GET), leading to delayed absorption and absorption kinetics amongst Indian Subjects. Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work current Cmax and tmax could not be compared to volume of distribution has been reported with earlier reports, due to non availability of data on lidocaine26, diazepam27 and ampicillin28 among cirrhotic patients. Current Vd increase in our group C patients, could also be due to the parallel with severity of disease. The increase in possible development of ascites during the AUC among the three type of cirrhosis could be course of the study. Our data of Vd correlate with explained due to decreased serum albumin level, earlier reports, suggesting that earlier studies hence affecting its binding to frusemide. The might have explored kinetics of frusemide in increase in AUC level could also be due to group C patients. Most data sources available, do decreased systemic clearance, responsible for the not distinguish between the types of diabetes, observed increase in volume of distribution and thereby rendering comparison with earlier half-life. The drug clearance in Group C is also further significantly reduced owing to a decrease in systemic clearance. The volume of distribution illustrative of the drug clearance from the body reported earlier22,23,24 correlated to some extent to were variable (Table 1). Whereas some studies that observed in our group C patients. This have reported decreased frusemide clearance indicates that earlier studies might have been among cirrhotic patients22,23,29, others have reported high clearance rate in compensated cirrhotics. The mean albumin levels among cirrhosis, and no difference in decompensated cirrhotics (3.55 ± 0.34 group A, 3.08 ± 0.22 groups24. Earlier reports did not mention about the stages of cirrhosis, thereby making it difficult respectively) in the current study were lower in to compare currently calculated values. As comparison to volunteers (4.75 ± 0.25). It has volume of distribution is inversely proportional been earlier reported that a decrease in protein to CL, our observations are justified by the observed increase in volume of distribution with justifying the increase in the volume of a paralleled decrease in systemic clearance distribution among cirrhotics. Similar trend in Table 1: Summary of reported kinetics of frusemide in cirrhotic patients (Nielsen 1973). It is also reported25 that clearance among A and B groups of cirrhosis vis cirrhotics have essentially no non renal a vis healthy volunteers indicates compensated stage. Compensated stage is expressed by a compensatory increase in renal excretion of Current kinetic parameters among healthy Indian detoxification capabilities of the liver24. The volunteers do not correspond to the earlier relatively decreased systemic clearance of the reports carried out mainly in Western countries. drug in group C cirrhosis may also be the result Such differences may be explained on various of higher age of patients in that category and basis such as the difference in techniques, aging, hence their associated dwindling renal functions sample selection, etc as explained above, but a Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work certain genetic interplay influencing drug venous obstruction. Methods Find Exp Clin disposition should not be ruled out. Genetic differences is becoming commonly known and 11. Kelly MR, Cutler RE, Forrey AW, et al. there are various approaches to create a ‘tailor made’ to reduce economic drug and curtail side Among Indian cirrhotic patients, the data 12. McCrindle JL, Li Kam Wa TC, Barron W, obtained could not be effectively compared to et al. Effect of food on the absorption of earlier studies due to lack of conclusive data on frusemide and bumetanide in man. Br J Clin the three types of cirrhosis. Thus our study was a pioneer study among the Indian subjects and also 13. Wolf-Coporda A, Lovric Z, Huic M, et al. in the various categories of cirrhosis. Moreover, kinetic trend among A, B and C type cirrhosis furosemide preparations; the effect of high could not be compared to earlier reported trends, which could possibly be influenced by genetic Williams EJ, Iredale JP. Liver cirrhosis. 16. Johansson LC, Frison L, Logren U, et al. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an Gines P, Fernandez-Esparrach G, Arroyo V. Ascites and renal functional abnormalities in 17. Shinkuma D, Hamaguchi T, Kobayashi M, bioavailability of sulpiride from AEA film- Puschet JB, Winaver J. Effects of diuretics on renal function. Handbook of physiology. dissolution characteristic in normal or drug- Oxfo0rd Universoty Press. 1992:2335-407. induced achlorhydric subjects. Int J Clin Kim EJ, Han KS, Lee MG. Gastrointestinal first-pass effect of furosemide in rats. J 18. Bradford CR, Prentice AG, Warnock DW, et administration in chronic liver disease. Drug itraconazole during remission induction for acute myeloblastic leukaemia. J Antimicrob British Medical Bulletin 1999;55(2):366-86. Colombo S, Buclin T, Cavassini M, et al. Intestinal dysfunction in liver cirrhosis: Its Population pharmacokinetics of atazanavir role in spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2001 Jun;16(6):607- 20. Gumurdulu Y, Yapar Z, Canataroglu A, et al. Gastric emptying time and the effect of fluconazole in patients with liver cirrhosis. J autonomic neuropathy.J Clin Gastroenterol 21. Ishizu H, Shiomi S, Kawamura E, et al. Gastric emptying in patients with chronic Pharmacokinetics of omeprazole in patients with liver cirrhosis and extrahepatic portal Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from Internet Journal of Medical Update, Vol. 3, No. 1, Jan-Jun 2008 Original Work 22. Gonzalez G, Arancibia A, Rivas MI, et al. 26. Thomson PD, Melmon KL, Richardson JA, Pharmacokinetics of furosemide in patients with hepatic cirrhosis. Eur J Clin Pharmacol advanced heart failure, liver disease, and renal failure in humans. Ann. Intern. Med 23. Verbeeck RK, Patwardhan RV, Villeneuve JP, et al. Furosemide disposition in cirrhosis. 27. Klotz U, Avant GR, Hoyumpa A, et al. The disposition and elimination of diazepam in 24. Traeger A, Hantze R, Penzlin M, et al. effects of furosemide in patients with liver 28. Lewis GP, Jusko WJ. Pharmacokinetics of cirrhosis. Int J Clin Pharmacol Ther Toxicol ampicillin in cirrhosis. Clin Pharmacol Ther 25. Allgulander C, Beermann B, Sjogren A. 29. Sawhney VK, Gregory PB, Swezey SE, et Frusemide pharmacokinetics in patients with Copyrighted by Dr. Arun Kumar Agnihotri. All right reserved Downloaded from


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