Furosemide pharmacokinetics and its relevance to ototoxicityNilima A Kshirsagar1, Sharadini A Dahanukar1, BP Shah2, KK Vora1, SM Karandikar1, Vidya N Acharya2, UK Sheth1
1 Department of Pharmacology, Seth G.S. Medical College, Parel, Bombay-400 012, India
2 Department of Medicine, Seth G.S. Medical College, Parel, Bombay-400 012, India
Our earlier studies have demonstrated a possible pharmacokinetic explanation for the rate dependent ototoxicity of furosemide. The present study was carried out to find out possible role of plasma protein levels and drug protein binding in furosemide pharmnacokinetics and toxicity. Twenty patients with different protein patterns were given furosemide intravenously at different rates and doses. Plasma furosemide levels were fluorimetrically estimated in serial blood samples. The results indicate that dose and rate of administration and extent of binding to plasma proteins alter furosemide pharmacokinetics and the chances of toxicity are greater in hypoproteinemic patients.
In the past few years large doses of intravenous furosemide have increasingly been used for the treatment of renal failure.  There have been several reports of transient hearing loss and tinnitus after intravenous infusion of high doses of furosemide.  With ethacrynic acid ototoxic effect seems to occur at more conventionally used doses.  With furosemide however, the ototoxic effect is not noted at low doses and it has been observed that it can be prevented by giving furosemide as a slow infusion. 
It is possible that the distribution of furosemide may vary depending on the rate and dose of administration and this may be responsible for the ototoxic effect. We therefore thought worthwhile to study furosemide pharmacokinetics given in different doses at different rates. Since the elimination pattern of a drug can give some idea about the distribution pattern of the drug, furosemide elimination pattern was studied.
Our earlier studies  conducted in cats have shown that a secondary rise, signifying initial entry in some other compartment and then re-entry into plasma compartment, occurs when the drug is given in high doses as a fast infusion but not when given in low doses or as a slow infusion. It is possible that this occurs because of a larger fraction of the drug remaining free-not bound to proteinwhen it is given in high doses and as fast infusion.
In the present work, we have studied furosemide pharmacokinetics in high and low doses in patients with normal and low plasma protein levels and with nor mal and abnormal kidney functions.
The study was carried out in 2 parts: Part-I: This involved giving furosemide in high doses to patients with chronic renal failure in their post-dialysis period. Four patients were given 25 mg/ kg furosemide over 1 hr. (high dose fast infusion), and four patients were given same dose over 4 hrs. (high dose slow infusion). The urine output in these patients, during furosemide infusion period, varied from 0-300 ml. in 24 hrs, Part-II: This involved giving furosemide low doses-80 mg (over 10 sets.) to normal and hypoproteinemic patients.
Part-II: (a) included four normal volunteers with normal plasma protein and normal kidney and liver function.
Part-II (b) included chronic renal failure patients with total serum proteins less than 6.5 gm% and albumin levels less than 2.5 gm%. These patients had abnormal renal functions as judged by their blood urea nitrogen and serum creatinine levels.
Part-II: (c) comprised of four patients, who had hypoproteinemia (total serum proteins <6.5% and serum albumin <2.5 gm%) but no renal dysfunction.
For both studies furosemide was given intravenously and blood samples with drawn from the antecubital vein before and 0, 1, 5, 10, 15, 30, 60, 120, 180 and 240 mins. after stopping the infusion.
Furosemide was estimated fluorimetrically by the method described by Haussler and Hajdu. 
Furosemide levels in plasma at different times are plotted on a semilog graph paper as log plasma concentrations vs time.
1. It is observed that a secondary rise in plasma levels occurs after high doses (25 mg,/kg) of furosemide (in chronic renal failure patient) whether it is given slowly or rapidly [Figure 1].
2. When furosemide is given in low doses (80 mg.) the secondary rise occurs only in patients with low plasma proteins presumably low plasma protein drug binding, but does not occur in volunteers with normal plasma proteins [Figure 2].
Our earlier  furosemide pharmacokinetic studies conducted in cats have demonstrated that a secondary rise occurs in the plasma level only after the drug is given in high doses as a fast infusion. This rise signifies an entry into some compartment producing high concentrations there initially and then a re-entry in plasma compartment as plasma concentrations start falling, producing a secondary rise in plasma. Such a sudden high concentration in some compartment may lead to toxicity such as ototoxicity (inner ear may be a part of the compartment). We postulated that when the drug is given in high doses as a fast infusion a substantial fraction of the drug may remain free, not bound to plasma proteins and therefore can enter compartments other than plasma, producing high concentrations there.
When the plasma protein and therefore protein drug binding is low, greater amount of free drug remains in plasma as in hypoproteinemic and chronic renal failure patients. Thus toxicity is likely to occur even when the drug is given slowly and at times even when given in low doses.
The results of the present study show that the secondary rise in plasma signifying entry into another compartment and then re-entry in plasma occur when the drug is given in high doses rapidly or slowly and in hypoproteinemic patients it occurs even when low: doses of furosemide are given.
We encountered a case of ototoxicity even when furosemide 25 mg/kg was given slowly (over 4 hours) as advised by other workers. 
Thus, changes in the free fraction of the drug in serum have important clinical implications particularly from the toxicity point of view. Such changes in the free fraction are particularly liable to occur in hypoproteinemic individuals with highly protein bound drugs like furosemide. 
Patient population in this country may be having low plasma protein-drug binding and therefore may be more susceptible to effects that may occur on account of low protein binding.
[Figure 1], [Figure 2]