Furosemide | Smyd Signal

Pharmacokinetics of furosemide in goats following intravenous, intramuscular, and subcutaneous administrations

1Department of Pharmacology, Faculty of

Pharmacy, University of Erzincan Binali Yıldırım, Erzincan, Turkey
2Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, Kastamonu, Turkey
3Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Afyon Kocatepe, Afyonkarahisar, Turkey
4Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Hatay Mustafa Kemal, Hatay, Turkey
5Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey

Correspondence
Kamil Uney, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, 42031, Turkey.
Email: [email protected]
Abstract
Furosemide, a loop diuretic drug, is recommended for use in cases of edema, ascites, congestive heart failure, toxicosis, and acute renal failure in goats. However, its phar- macokinetics and bioavailability have not been reported yet in this species. The aim of this study was to determine the pharmacokinetics and bioavailability of furosemide in goats following intravenous (IV), intramuscular (IM), and subcutaneous (SC) admin- istrations at a dose of 2.5 mg/kg. Six clinically healthy goats received furosemide by each route in a three-way crossover pharmacokinetic design with a 15-day washout period between administrations. The plasma concentrations of furosemide were de- termined using the high-performance liquid chromatography-UV method and ana- lyzed by non-compartmental analysis. The elimination half-life following IV, IM, and SC administration was 0.71 (0.67–0.76) h, 0.69 (0.61–0.74) h, and 0.70 (0.67–0.79) h, respectively. The volume of distribution at steady state and total clearance for the IV route were 0.17 (0.16–0.19) L/kg and 0.30 (0.27–0.33) L/h/kg, respectively. The peak plasma concentrations of furosemide following IM and SC administrations were 11.19 (10.33–11.95) and 6.49 (5.92–7.00) μg/ml at 0.23 (0.16–0.25) and 0.39 (0.33– 0.42) h, respectively. The bioavailability was 109.84 (104.92–116.99)% and 70.80 (55.77–86.67)% for the IM and SC routes, respectively. The pharmacokinetics of furo- semide following the IV, IM, and SC administrations in goats demonstrated significant differences, which may have clinical and toxicological implications requiring further investigations.

K E Y W O R D S
bioavailability, Furosemide, goats, pharmacokinetics

1| INTRODUCTION

Furosemide is a loop diuretic drug used in the fields of human and veterinary medicine. Furosemide exhibits its effects by inhibiting the luminal Na+/K+/2Cl- transporter protein in the thick ascending limb of Henle loop (Pacifici, 2013; Shaheen et al., 2013). Furosemide increases the urinary excretion of elements such as magnesium, calcium, potassium, and ammonium, mainly sodium and chloride (Carone et al., 2016; Pacifici, 2013). In addition to its diuretic effect,

furosemide stimulates prostaglandin (PG) E2 synthesis, thereby in- creasing renal and extra-renal vascular effects in the kidney as well as decreasing inflammatory mediators such as leukotrienes and his- tamine in the lung (CVMP, 1999; Kandasamy & Carlo, 2017).
The use of furosemide in cases of edema, renal failure with oli- guria and intoxication is approved by European Medicines Agency (EMA) in cattle, pigs, and horses (CVMP, 1999). Moreover, furosemide has been recommended in volume-overload cases and intoxication in cats and dogs (Kochevar, 2009). Furosemide is recommended for

use in cases of edema (pulmonary, cerebral, and udder), ascites, con- gestive heart failure, toxicosis, and acute renal failure in goats (Fajt
& Pugh, 2012; Smith & Sherman, 2009a, 2009b). Pharmacokinetics of furosemide has been reported in pigs (Miceli et al., 1990), dogs (Hirai et al., 1992), camels (Ali et al., 1998), horses (Dyke et al., 1996), cats (Sleeper et al., 2019), and sheep (Durna Corum et al., 2020). However, despite the potential of therapeutic use of furosemide in goats (Fajt & Pugh, 2012; Smith & Sherman, 2009a, 2009b), its pharmacokinetics and bioavailability have not been reported yet in goats. We hypothesized that alternative administration routes of furosemide in goats would be used by the presentation of good bio- availability after intramuscular (IM) and subcutaneous (SC) routes, which are more practical and frequently used in the clinical setting. Therefore, this study aimed to determine the pharmacokinetics and bioavailability of furosemide following intravenous (IV), IM, and SC single-dose administration in goats at a dose of 2.5 mg/kg.

2| MATERIALS AND METHODS

2.1| Animals

The study was carried out on 6 female goats (2.4 ± 0.4 years and 45 ± 5 kg of body weight) determined to be healthy by general clinical examination, complete blood count, and serum biochemis- try panel. Goats were animals housed and fed in a commercial farm (Iskenderun/Hatay). They had not received other medications in the past 1 month. All goats were housed in the animal shed with concrete floor (40 m2) within 2 weeks before the study for adaptation. The goats had free access to water and were fed with drug-free commer- cial feed and alfalfa hay. The experiment was approved (2020/02-3) by the Local Ethics Committee for Animal Research Studies at Hatay Mustafa Kemal University (Hatay/Turkey).

2.2| Experimental design

The study was carried out according to the crossover design in three periods, with a 15-day washout period between administrations. Furosemide (Lasix, 20 mg/ml, Sanofi Aventis) was administered at a dose of 2.5 mg/kg. Each goat received single IV (left jugular vein), IM (between the semitendinosus and the semimembranosus muscles), and SC (the axillary region) injections of furosemide with 15-day washout period. In the first period, furosemide was administered via IV to 2 goats, IM to 2 goats, and SC to 2 goats. In the second and third periods following the 15-day washout period, each goat received furosemide via different routes of administration. Blood samples (2 ml) were collected into heparin-containing anticoagulant
2.3| HPLC and chromatographic conditions

Furosemide concentrations in the plasma samples of goat were ana- lyzed by the high-performance liquid chromatography (HPLC)-UV system (Shimadzu) with the previously described method (Durna Corum et al., 2020; Lin et al., 1979). 200 μl of plasma sample was added to 1.5 ml micro-centrifuge tubes. Then, 400 μl methanol (Merck) was added and vortexed for 45 s, followed by centrifuga- tion at 10 000 g for 15 min. The supernatant was transferred into auto-sampler vials, and 10 μl was injected into the HPLC-UV sys- tem. The HPLC system consists of a pump (LC-20AT controlled by the CBM-20A), a degasser (DGU-20A), an auto-sampler (SIL 20A), and column oven (CTO-10A). For detection of furosemide, a SPD- 20A UV-VIS detector set to 280 nm wavelength and a Gemini C18 column (250 × 4.6 mm; internal diameter, 5 μm; Phenomenex) were used. The column and auto-sampler temperatures were maintained at 40°C and 24°C, respectively. The mobile phase comprised metha- nol (35%) and 0.01 M sodium acetate (pH:5.65%, Merck, Darmstadt, Germany) was transferred to the HPLC with a flow rate of 1 ml/min.
Validation was carried out according to EMA (2011) guidelines for the chromatographic method. The stock solution (100 μg/ml) of furosemide (analytical standard, ≥99%, Sigma–Aldrich) prepared in methanol was diluted to prepare calibration standards (0.04– 40 μg/ml) and quality control samples (0.4, 4 and 40 µg/ml). The calibration curve provided excellent linearity with a correlation co- efficient r2 > .9994 within the range of the calibration curve from 0.04 to 40 μg/ml. The lower limit of quantification was 0.04 µg/
ml for furosemide in goat plasma with the coefficient of variation less than 20% and the bias of ±15%. The mean recoveries of furo- semide determined over the concentrations of 0.4, 4, and 40 µg/
ml were 96, 93, and 92%, respectively. The coefficient of variation calculated from three quality control samples for intraday and in- terday precision was <8%. The intraday and interday bias of accu- racy was ±7%.

2.4| Pharmacokinetic calculations

Plasma concentrations of furosemide were analyzed by a non- compartmental method using WinNonlin 6.1.0.173 software pro- gram (Pharsight Corporation, Scientific Consulting Inc.). Following IV administration, the area under the concentration versus time curve (AUC), the slope of the terminal phase of the plasma drug concentration profile (λz), terminal elimination half-life (t1/2ʎz), mean residence time (MRT), total clearance (ClT), and volume of distribu- tion at steady state (V ) were calculated. The λz is estimated as
dss
the absolute values from >3 data points using a log-linear regres- sion analysis. The t1/2λz was calculated as ln (2)/λz. The AUCIV and

tubes via the catheter from the right jugular vein of each goat at 0 AUCIM,SC were estimated using the linear/log trapezoidal method

(pre-treatment), 5, 10, 15, 20, 25, 30, and 45 min and 1, 1.5, 2, 3, 4, 5, and 6 hours following drug administration. All blood samples were centrifuged at 4000 g for 10 min, and the separated plasma was stored at -80°C until analysis.
and the linear up/log down method. The ClT was calculated as the dose divided by AUC0–∞. The area under the first-moment curves (AUMC) was defined as the area under the curve of the product of time and the plasma drug concentration versus time from time zero

to infinity. The MRT was calculated as AUMC0–∞/AUC0–∞. The Vdss after IV administration was calculated as (MRTIVxClT), Following IM and SC administration, AUC and t1/2ʎz were calculated. The mean ab- sorption time (MAT) was calculated as MRTIM,SC – MRTIV. The peak plasma concentration (Cmax) and time to reach the Cmax (Tmax) were obtained directly from the plasma concentration–time curve foreach goat. Bioavailability was calculated by means of the following for- mula: F = (AUCIM,SC/AUCIV) × 100. The extraction ratio (Ebody) for furosemide after IV administration was calculated according to the following formula:

Ebody = CLT ∕QC ,

FI G U R E 1 Semi-logarithmic plasma concentration–time curves

where QC (ml/kg/min) is the cardiac output calculated according to the allometric equation (Toutain & Bousquet-Melou, 2004a):

QC = 180BW – 0.19 ,

where BW stands for body weight (kg) of each animal.

2.5| Statistical analysis

Statistical analyses were performed using SPSS 22.0 program (IBM Corp). Data were presented as the geometric mean (min–max). The t1/2ʎz and AUC after IV, IM, and SC administration were evaluated using Friedman test and post hoc Wilcoxon signed-rank test. The MRT, MAT, Cmax, Tmax, and bioavailability after IM and SC adminis- tration were analyzed using Wilcoxon signed-rank test. Values of p < 0.05 were considered significant.

3| RESULTS

All goats remained in good health (behavior, feed and water con- sumption, and fecal production) during the acclimatization and experimental period. In this study, all the animals received the left dosage of furosemide for all routes. There were no local adverse ef- fects at the injection site such as pain, redness, and lameness after IV, IM, and SC administration of furosemide. The semi-logarithmic plasma concentration–time curves and pharmacokinetic parameters of furosemide following IV, IM, and SC administrations at a dose of 2.5 mg/kg in the goats are presented in Figure 1 and Table 1, respec- tively. The t1/2ʎz for IV, IM, and SC administration was not statisti- cally different among administration routes. The AUC0-∞ obtained following IV and IM administration was higher than that following SC administration. The ClT and Vdss after IV administration were 0.30 (0.27–0.33) L/h/kg and 0.17 (0.16–0.19) L/kg, respectively. The Cmax of furosemide following IM and SC administrations was 11.19 (10.33–11.95) and 6.49 (5.92–7.00) μg/ml at 0.23 (0.16–0.25 h) and 0.39 (0.33–0.42 h) hours, respectively. Following IM and SC ad- ministrations, the bioavailability was 109.84 (104.92–116.99)% and 70.80 (55.77–86.67)%, respectively. The Ebody of furosemide for IV
of furosemide following intravenous (IV), intramuscular (IM), and subcutaneous (SC) administrations at a dose of 2.5 mg/kg in goat (n = 6, mean ± SD)

administration was 0.056 (0.052–0.062). The percentage AUC ex- trapolated values for all routes were <20%.

4| DISCUSSION

Furosemide dose is wide range in sheep (1–6 mg/kg, Blaze & Glowaski, 2004; Fajt & Pugh, 2012; Jones, 2001), cattle (0.5–5 mg/kg, CVMP, 1999; Underwood et al., 2015), horse (0.5 to 1 mg/animal or 1–4 mg/
kg, Blaze & Glowaski, 2004; CVMP, 1999), and pigs (2 to 5 mg/kg, Blaze & Glowaski, 2004; CVMP, 1999) to treat excessive fluid accu- mulation (edema) in body caused by conditions such as congestive heart failure, liver disease, and renal disease and for diuresis in intoxi- cations, renal failure with oliguria and diagnostic tests. Additionally, furosemide dose in goats ranged from 1 mg/kg for the treatment of cerebral edema and acute renal failure to 10 mg/kg for the treatment of udder edema (Blaze & Glowaski, 2004; Boesch et al., 2009; Fajt &
Pugh, 2012; Hahn, 2019; Laus et al., 2011; Fajt & Pugh, 2012; Smith
& Sherman, 2009a, 2009b). In this study, furosemide dose (2.5 mg/
kg) was selected within the dose range of 1 to 10 mg/kg recom- mended in goats (Blaze & Glowaski, 2004; Boesch et al., 2009; Fajt &
Pugh, 2012; Hahn, 2019; Laus et al., 2011; Fajt & Pugh, 2012; Smith
& Sherman, 2009a, 2009b). Furosemide is often used via IV and IM administration (CVMP, 1999). However, the lesions occurred in the injection area due to IM administration in meat-producing animals might constitute a disadvantage (Constable et al., 2017). It has been noted that the efficacy of furosemide following SC injection in dogs is similar to IV administration and can be used as an alternative to IV ad- ministration (Harada et al., 2015). Therefore, the SC injection, which is the widely preferred route of drug administration due to a higher injection volume and a larger injection area in goats, may be preferred as an alternative route of administration of furosemide as depending on the injection volume of the drug.
The t1/2ʎz, Vdss, and ClT after IV administration of furosemide in goats were 0.71 (0.67–0.76) h, 0.17 (0.16–0.19) L/kg, and 0.30 (0.27– 0.33) L/h/kg, respectively. These values were toward the lower start

Parameter

SC
TA B LE 1 Plasma pharmacokinetic parameters of furosemide following

t
1/2ʎz
(h)
0.71 (0.67–0.76)
0.69(0.61–0.74)
0.70(0.67–0.79)
intravenous (IV), intramuscular (IM), and

AUC
AUC
0-4
0-∞
(h*µg/ml) 8.38 (7.53–9.20)
(h*µg/ml) 8.46 (7.59–9.29)
9.16 (8.70–9.87) 9.29 (8.83–10.06)
5.88# (5.09–6.69) 5.99# (5.18–6.80)
subcutaneous (SC) administrations at a dose of 2.5 mg/kg in goats (n = 6)

AUCextrap (%) 0.93 (0.78–1.09) 1.37 (0.84–1.90) 1.81 (1.45–2.59)
MRT0-∞ (h) 0.59 (0.55–0.63) 0.89 (0.81–0.96) 1.04* (0.98–1.07)
MAT (h) – 0.30 (0.20–0.37) 0.45* (0.37–0.50)
ClT (L/h/kg) 0.30 (0.27–0.33) – –
Vdss (L/kg) 0.17 (0.16–0.19) – –
Cmax (µg/ml) – 11.19 (10.33–11.95) 6.49* (5.92–7.00)

T
max
(h)
–
0.23 (0.16–0.25)
0.39* (0.33–0.42)

F (%) – 109.84 (104.92–116.99) 70.80* (55.77–86.67)
Note: Data were presented as the geometric mean (min–max).
AUC extrapolated %, area under the plasma concentration–time curve extrapolated from tlast to
∞ in of the total AUC; AUC, area under the plasma concentration–time curve; ClT, total clearance; Cmax, peak concentration; F, bioavailability; MAT, mean absorption time; MRT, mean residence time; t1/2ʎz, elimination half-life; Tmax, time to reach peak concentration; Vdss, volume of distribution at steady state.
#Value is statistically different than that in IV and IM administrations (p < .05). *Value is statistically different than that in IM administration (p < .05).

of the range of t1/2ʎz (from 0.51 to 3.42 h), Vd (from 0.17 h to 0.65 L/
kg), and ClT (from 0.15 to 0.9 L/h/kg) previously reported in other domestic species (Ali et al., 1998; Durna Corum et al., 2020; Dyke et al., 1996; Hirai et al., 1992; Johansson et al., 2004; Knych et al., 2018; Miceli et al., 1990; Miyazaki et al., 1990; Sleeper et al., 2019). In this study, the Ebody of furosemide for IV administration in goats was calculated as 0.056 (0.052–0.062), which exhibited a low ex- traction ratio of furosemide. The Ebody of furosemide would be clas- sified as low in sheep (Durna Corum et al., 2020), camels (Ali et al., 1998), dogs (Hirai et al., 1992), and cat (Sleeper et al., 2019), because it is around 0.05, but medium in horses (Dyke et al., 1996; Johansson et al., 2004), because it is around 0.15 (Toutain & Bousquet-Melou, 2004a). This may indicate that sheep, goats, camels, dogs, and cats have the same ability to eliminate furosemide (Toutain & Bousquet- Melou, 2004a). The binding ratio of furosemide to plasma proteins in goats remains unknown, but in some animal species (horse, bovine, dog, and rabbit), it ranges from 87% to 98.1% (Johansson et al., 2004; Prandota & Pruitt, 1991). Due to the difference in the binding ratio of furosemide to plasma proteins in piglets of different age groups (3–18 days), the distribution volume has been reported to change (0.20–0.62 L/kg) (Miceli et al., 1990). Additionally, body composition affects the pharmacokinetics of drugs (Modric & Martinez, 2011). The reason of lower Vdss in goats according to other animal species may be the difference in binding ratio to plasma proteins and body composition. Furosemide elimination from the body significantly dif- fers among animal species. In some animal species (horse, cattle, dog, and rat), the excretion of furosemide through the urine and feces varies between 16%–89.1% and 5.4%–54%, respectively (CVMP, 1999; Hirai et al., 1992; Villarino et al., 2019). Furosemide is metab- olized in the liver and kidney, and 50%–85% is excreted unchanged in the urine in horses, dogs, monkeys, and pigs (CVMP, 1999; Miceli
et al., 1990; Villarino et al., 2019). The variability of elimination of furosemide between species may be owing to its difference in me- tabolism and excretion processes.
After the administration of furosemide via IV, IM, and SC routes in goats, the t1/2ʎz was 0.71 (0.67–0.76), 0.69 (0.61–0.74), and 0.70 (0.67–0.79) h, respectively, and there was no significant differ- ence between the routes of administration. The t1/2ʎz of furose- mide were similar for different administration routes in camels (IV; 1.96 h, IM; 1.82 h, Ali et al., 1998) and sheep (IV; 0.79 ± 0.04 h, IM; 0.80 ± 0.05 h, SC; 0.80 ± 0.02 h, Durna Corum et al., 2020). In this study, the MAT and MRT after SC administration were longer than those after IM administration. The MATSC longer than MATIM in goats suggested a slow absorption of furosemide after SC admin- istration. Because MRT for extravascular route includes MAT, the extended MRT for SC route in goats may be due to slow absorption of furosemide.
In goats, the bioavailability of furosemide after SC administra- tion was 70.80 (55.77–86.67)%, which was higher than that in sheep (38%, Durna Corum et al., 2020). In this study, the bioavailability of furosemide after IM administration was good with 109.84 (104.92– 116.99)%. The good bioavailability of furosemide after IM adminis- tration has been also reported in camels (71%, Ali et al., 1998) and sheep (97.91 ± 10.44%, Durna Corum et al., 2020). In this study, the bioavailability of furosemide after IM administration in goats was 109.84 (104.92–116.99)%, which was close to 100%. Reasons includ- ing experimental errors (e.g., analytical artifacts, vehicle effects) and common mechanistic explanations (e.g., nonlinear pharmacokinetics, inter-occasion variability for clearance) might cause to bioavailability higher than 100% (Toutain & Bousquet-Melou, 2004b). In this study, when experimental errors are ruled out following control, the non- linear pharmacokinetics and inter-occasion variability for clearance

might have result in the observed bioavailability higher than 100%. However, furosemide exhibited linear pharmacokinetics for doses up to 50 mg/kg in dogs (Brown, 1981). Goats received furosemide ac- cording to the crossover design in three periods, with a 15-day wash- out period between administrations. The inter-occasion variability for clearance, with a real bioavailability close to 100%, might have result in the observed bioavailability higher than 100%. The Cmax of furo- semide after IM administration in goats was 11.19 (10.33–11.95) µg/
ml, which was similar to that reported in sheep (10.33 ± 0.63 µg/ml, Durna Corum et al., 2020) and higher than dose-normalized value (3.5 µg/ml at 2.5 mg/kg) in camels (Ali et al., 1998). The Tmax of IM route in goats was 0.23 (0.16–0.25) h, which was similar to that re- ported in camels (0.25 h, Ali et al., 1998) and sheep (0.33 h, Durna Corum et al., 2020). In goats, the Cmax of furosemide following SC ad- ministration was 6.49 (5.92–7.00) μg/ml, which was higher than that in sheep (3.18 ± 0.24 μg/ml, Durna Corum et al., 2020), but Tmax of SC route in goats (0.39 h) was similar to that in sheep (0.42 h, Durna Corum et al., 2020).
The effect of furosemide is dose dependent, and the plasma concentration required for half maximum diuretic activity is 1 and 1.5 µg/ml in humans and dogs, respectively (Hirai et al., 1992; Miyazaki et al., 1990). Additionally, it has been noted that when the plasma concentration of furosemide is above 10 µg/ml, the diuretic effect may decrease and furosemide may cause ototoxicity when it is above 25 µg/ml (CVMP, 1999; Hirai et al., 1992; Kandasamy & Carlo, 2017). However, because furosemide reaches to luminal action site via secretion by organic acid transport system of proximal tubule, large doses of furosemide in patients with reduced renal function are administered to provide sufficient secretion of drug to urine by increasing plasma concentrations (Volker et al., 1987). When large doses (<2000 mg/day) of furosemide in human are administered, oral and slow infusion administrations have been recommended to reduce toxicity (Pacifici, 2013). In this study, after the rapid (0.5 min) IV bolus injection of 2.5 mg/kg in goats, the plasma concentration of furosemide from 0.08 h (at the first sampling time) to 0.25 h de- creased from 19.03 ± 2.16 µg/ml to 9.48 ± 0.66 µg/ml. The plasma concentration of furosemide after IV, IM, and SC administration at a dose of 2.5 mg/kg in goats was above 1 µg/ml at 1, 1.5, and 1.5 h, respectively. These data show that furosemide at 2.5 mg/kg dose provides the necessary plasma concentration to exhibit a diuretic effect in all routes of the administration in goats. However, possible side effects of furosemide related to the high plasma concentration obtained after the rapid (0.5 min) IV bolus injection would likely de- crease with the slow rate of bolus injection, or the continuous infu- sion of furosemide.
In conclusion, our results showed that the plasma concentration and bioavailability of furosemide changed according to the adminis- tration route. Despite the differences found, the time that furose- mide concentration remains above minimum effective concentration (≥1 µg/ml) is similar for IV, IM, and SC injection, thereby using as suitable routes for diuresis in goats. However, the IV route may be administered via slow bolus injection or continuous infusion to de- crease possible side effects of furosemide related to the high plasma

concentration obtained after the rapid IV bolus injection. The differ- ences among routes of administrations may have clinical and toxico- logical implications requiring further investigations.

CONFLICT OF INTEREST
All authors declare that they have no conflicts of interest.

AUTHOR CONTRIBUTION
All authors have read and approved the final manuscript. GC, OC, DDC, and KU contributed to conception, experimental design, and analysis, drafted the manuscript, critically revised the manuscript, provided final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. OA, IOT, and ET contrib- uted to conception and design.

ANIMAL WELFARE STATEMENT
The experiment was approved (2020/02-3) by the Local Ethics Committee for Animal Research Studies at Hatay Mustafa Kemal University (Hatay/Turkey) and carried out in accordance with the European Directive (2010/63/UE).

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

ORCID
Gul Cetin https://orcid.org/0000-0002-9408-0042 Orhan Corum https://orcid.org/0000-0003-3168-2510
Duygu Durna Corum https://orcid.org/0000-0003-1567-991X Orkun Atik https://orcid.org/0000-0003-2411-7492
Erdinc Turk https://orcid.org/0000-0003-1735-1774
Ibrahim Ozan Tekeli https://orcid.org/0000-0002-6845-2279 Kamil Uney https://orcid.org/0000-0002-8674-4873

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How to cite this article: Cetin, G., Corum, O., Durna Corum, D., Atik, O., Turk, E., Tekeli, I. O., & Uney, K. (2021). Pharmacokinetics of furosemide in goats following intravenous, intramuscular, and subcutaneous administrations. Journal of Veterinary Pharmacology and Therapeutics, 00, 1–6. https://doi.org/10.1111/jvp.13009