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wileyonlinelibrary.com/journal/jvp © 2019 John Wiley & Sons Ltd J vet Pharmacol Therap. 2019;42:624–631. Received: 5 April 2019|
Revised: 5 May 2019|
Accepted: 14 May 2019DOI: 10.1111/jvp.12787
P H A R M A C O K I N E T I C R E P O R T
Pharmacokinetics of enrofloxacin and danofloxacin in
premature calves
Orhan Corum
1| Feray Altan
2| Ramazan Yildiz
3| Merve Ider
4| Mahmut Ok
4|
Kamil Uney
51Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, Kastamonu, Turkey
2Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Dicle, Diyarbakir, Turkey
3Department of Internal Medicine, Faculty
of Veterinary Medicine, University of Mehmet Akif Ersoy, Burdur, Turkey
4Department of Internal Medicine, Faculty
of Veterinary Medicine, University of Selcuk, Konya, Turkey
5Department of Pharmacology and
Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey
Correspondence
Orhan Corum, Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Kastamonu, Kastamonu, Turkey.
Email: orhancorum46@hotmail.com
Abstract
The aim of this study was to determine the pharmacokinetics/pharmacodynamics of enrofloxacin (ENR) and danofloxacin (DNX) following intravenous (IV) and intramus‐ cular (IM) administrations in premature calves. The study was performed on twenty‐ four calves that were determined to be premature by anamnesis and general clinical examination. Premature calves were randomly divided into four groups (six prema‐ ture calves/group) according to a parallel pharmacokinetic (PK) design as follows: ENR‐IV (10 mg/kg, IV), ENR‐IM (10 mg/kg, IM), DNX‐IV (8 mg/kg, IV), and DNX‐IM (8 mg/kg, IM). Plasma samples were collected for the determination of tested drugs by high‐pressure liquid chromatography with UV detector and analyzed by noncom‐ partmental methods. Mean PK parameters of ENR and DNX following IV administra‐ tion were as follows: elimination half‐life (t1/2λz) 11.16 and 17.47 hr, area under the plasma concentration–time curve (AUC0‐48) 139.75 and 38.90 hr*µg/ml, and volume of distribution at steady‐state 1.06 and 4.45 L/kg, respectively. Total body clearance of ENR and DNX was 0.07 and 0.18 L hr−1 kg−1, respectively. The PK parameters of
ENR and DNX following IM injection were t1/2λz 21.10 and 28.41 hr, AUC0‐48 164.34 and 48.32 hr*µg/ml, respectively. The bioavailability (F) of ENR and DNX was deter‐ mined to be 118% and 124%, respectively. The mean AUC0‐48CPR/AUC0‐48ENR ratio was 0.20 and 0.16 after IV and IM administration, respectively, in premature calves. The results showed that ENR (10 mg/kg) and DNX (8 mg/kg) following IV and IM administration produced sufficient plasma concentration for AUC0‐24/minimum in‐ hibitory concentration (MIC) and maximum concentration (Cmax)/MIC ratios for sus‐ ceptible bacteria, with the MIC90 of 0.5 and 0.03 μg/ml, respectively. These findings may be helpful in planning the dosage regimen for ENR and DNX, but there is a need for further study in naturally infected premature calves.
K E Y W O R D S
bioavailability, danofloxacin, enrofloxacin, pharmacokinetics, premature calves
1 | INTRODUCTION
Parturition involves changes in the physiologic and metabolic func‐ tions of many major organs in the offspring needed for extrauterine
survival (Sangild, 2006; Silver, 1990). Fetal glycogen and cortico‐ steroid levels markedly increase prepartum in different mammalian species, including cattle. The increased glycogen and corticosteroid levels in turn stimulate the maturation events in many essential
organs, such as the lung, liver, kidney, and gastrointestinal tract in fetus (Silver, 1990). Calves born at a gestational age of 230–260 days are defined as premature, and many organs are not fully mature (Karapinar & Dabak, 2008). Because of immaturity, the ability to cope with infections may be impaired in calves, and premature calves may be predisposed to serious health problems (Aydogdu, Yildiz, Guzelbektes, Coskun, & Sen, 2016; Bittrich et al., 2004). As premature calves have weak or absent suckling reflexes, they cannot take colostrum in sufficient amounts (Yildiz & Ok, 2017). Premature calves, due to the failure of passive transfer, have a higher risk of infectious diarrhea, pneumonia, sepsis, and abnormal pulmonary functions than mature calves (Bleul, 2009; Weaver, Tyler, VanMetre, Hostetler, & Barrington, 2000; Yildiz & Ok, 2017). Because of the im‐ mature immune system, and the insufficiency of passive transfer of maternal antibodies, drugs with bactericidal activity are a preferred treatment for premature calves (Hulbert & Moisá, 2016; Schmidt, Sangild, Blum, Andersen, & Greve, 2004).
Enrofloxacin (ENR) and danofloxacin (DNX) are fluoroquinolones approved for veterinary use in Europe for treatment of some infec‐ tions caused by Mycoplasma bovis (M. bovis) (Brown, 1996), Pasteurella
multocida (P. multocida), and Escherichia coli (E. coli) in calves (Constable,
2004; McKellar, Gibson, Monteiro, & Bregante, 1999). However, these drugs are not approved use in the treatment of calf diarrhea caused by susceptible bacteria in the United States (Constable, 2004). Both ENR and DNX have exhibited pharmacokinetic (PK) properties such as a large volume of distribution, long elimination half‐life, and high bioavailability in calves (Daundkar, Vemu, Dumka, & Sharma, 2015; McKellar et al., 1999). Furthermore, ENR is partially metabolized to ciprofloxacin (CPR), which exhibits a potency and spectrum of activity similar to ENR, in calves (Davis, Foster, & Papich, 2007).
The PK and PD (pharmacodynamic) characteristics of antimi‐ crobial drugs need to be more fully described to allow informed decisions concerning dosage selection. The area under the plasma concentration–time curve (AUC)/minimum inhibitory concentration (MIC) and maximum concentration (Cmax)/MIC ratios are the main PK‐PD parameters used for evaluating the effectiveness of con‐ centration‐dependent antimicrobial drugs such as fluoroquinolones (McKellar, Sanchez Bruni, & Jones, 2004). The administration of ENR or DNX may be effective for the treatment of bacterial infection in premature calves (Kaartinen, Pyörälä, Moilanen, & Räisänen, 1997; Sunderland, Sarasola, Rowan, Giles, & Smith, 2003). However, the lack of data regarding the PK of ENR or DNX in premature calves makes rational dosage regimens of these drugs difficult in premature calves. For these reasons, the conclusions of this research may be useful for optimizing the use of ENR or DNX to treat bacterial in‐ fections in premature calves. Premature birth interrupts maturation of prenatal organs, including the lungs, the liver, the cardiovascular system, the kidneys, and the gastrointestinal tract (Sangild, 2006). These situations may cause major changes in body composition and metabolic capacity, both of which can impact the PK and PD of drugs used in premature animals. The safe and effective dosage regimens for any antimicrobial drug used in the treatment of infections in pre‐ mature animals have not yet been defined in veterinary medicine.
In premature animals, changes in the PK and PD of a drug can be expected as the organs are not completely developed. Previous studies suggest that further investigation is needed to better under‐ standing the PK and PD relationships of ENR or DNX in premature calves (Balaje, Sidhu, Kaur, & Rampal, 2013; de Lucas, San Andrés, González, Froyman, & Rodríguez, 2008; McKellar et al., 1999). For fluoroquinolones, the AUC0‐24/MIC has generally been mentioned as the most significant PK/PD parameter related to bactericidal ef‐ fects, but the Cmax/MIC has also been recommended as important for avoiding the development of resistance (Martinez, McDermott, & Walker, 2006; Papich, 2014).
The aims of this study were (a) to determine the PK of ENR and DNX in premature calves and (b) to integrate the PK parameters ob‐ tained from this study and MIC values obtained in previous studies. This information will facilitate recommendations regarding ENR and DNX dosing for treating susceptible pathogens in premature calves.
2 | MATERIAL AND METHODS
2.1 | Chemicals and reagents
Commercial ENR, CPR, and DNX standards, high‐performance liquid chromatography (HPLC) grade acetonitrile (ACN), triethylamine, and orthophosphoric acid were supplied by Sigma‐Aldrich. Parenteral formulations of ENR (Baytril® 10% injectable solution; Bayer) and DNX (Advocin®, 25 mg/ml, injectable solution; Zoetis) were used for intravenous (IV) and intramuscular (IM) administrations.
2.2 | Animals
Experimental procedures were approved by the Ethics Committee of the University of Selcuk (Konya, Turkey, Ethics Commission, per‐ mit 76/2015). The study was performed on 24 Holstein calves (12 males, 12 females, weighing between 17 and 23 kg) that were found to be premature by the anamnesis and general clinical examination. The calves which were found to be born prematurely according to predetermined criteria (gestational age between 245 and 260 days, low body weight, weak or no suckling reflex, short silky hair coat, incomplete eruption of the incisor teeth, soft claws, and general weakness) as described by Yildiz and Ok (2017) and Guzelbektes, Coskun, Ok, Aydogdu, and Sen (2012) were included in this study. Calves were fed the fresh or frozen colostrum (10% of body weight) daily. Colostrum was administered through a stomach tube to calves, which had a weak suckle reflex. Standard treatment as previously described by Yildiz and Ok (2017), including oxygen therapy (5–6 L/ min per calf via a mask), supportive treatment [vitamin ADE (1 ml/ day, IM, Ademin®, Ceva‐Dif, Turkey), calcium (0.2 ml kg‐1 day‐1, SC, Kalsimin®, Vilsan, Turkey), phosphorus (3 ml/day, SC, Fosfotonik®, Topkim, Turkey), and vitamin C (3 ml/day, SC, Cevit®, Biovita, Turkey) were administered for 3 days, while a single dose of selenium vi‐ tamin E (1 ml, IM) (Yeldif®, Ceva‐Dif, Turkey) was administered to each calf], and clinical care (sternal position bed, towels, etc.) were provided to each calf in all treatment groups.
2.3 | Study design and dosage forms
Before the start of this study, premature calves were randomly divided into four groups, according to a parallel PK group design. Each group consisted of six premature calves (three male and three female) as fol‐ lows: Group ENR‐IV was treated with ENR intravenously, group ENR‐IM was treated with ENR intramuscularly, group DNX‐IV was treated with DNX intravenously, and group DNX‐IM was treated with DNX intramus‐ cularly. The PKs of ENR at dose of 10 mg/kg and DNX at dose of 8 mg/ kg after IM and IV administration were studied in premature calves.
For IM administrations, the drugs were injected in the lower third region of the neck. For IV administrations, the drugs were admin‐ istered via an IV catheter (22 G, 0.9 × 25 mm, Bicakcilar Medical Devices Industry and Trade Co.) placed in the vena jugularis imme‐ diately prior to treatment. Blood samples were collected prior to treatment (0 hr) and 15, and 30 min, and 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hr after drug administration. Samples (2 ml) were col‐ lected into heparinized test tubes by a catheter placed in the jugular vein contralateral to that used for drug administration. The blood tubes were protected from light and were centrifuged at 4,000 g for 10 min and stored at −70°C until analysis.
2.4 | HPLC analysis
Plasma samples were assayed using HPLC with ultraviolet detection (UV) according to a previously reported method (Real et al., 2011; Ruennarong et al., 2016). Plasma samples (200 µl) were added to 400 µl of ACN. The samples were vortexed for 30 s and centrifuged at 10,000 g for 10 min. After centrifugation of samples, the 100 µl of HPLC grade water was added to 100 µl of the supernatant. A total of 200 µl of clear supernatant was pipetted to an autosam‐ pler vial, and 10 μl of the supernatant was injected into the HPLC system. The HPLC system was controlled using a Shimadzu‐LC system (Shimadzu) equipped with a CBM‐20A controller, equipped with a pump (LC‐20AT), a degasser (DGU‐14A), an ultraviolet detec‐ tor (SPD‐10A UV‐VIS), an autosampler (SIL‐20A), and a column oven (CTO‐10A) to analyze ENR, CPR, and DNX. Chromatographic sepa‐ ration was performed using a Gemini™ C18 column (250 × 4.6 mm; internal diameter, 5 µm; Phenomenex). The column and autosampler temperatures were at 40°C and room temperature, respectively. The mobile phase consisted of 17% ACN and 83% aqueous solution (HPLC grade water containing 0.4% orthophosphoric acid and 0.4% triethylamine) at a flow rate of 1 ml/min. The LC solution software program (Shimadzu, Japan) running on an Asus PC was used for in‐ strument control and data analysis.
The assay of calibration standards for ENR was linear with a cor‐ relation coefficient of >0.9996 over the concentration range of 0.01– 10 µg/ml. Plasma recovery ranged from 90.56% to 99.60%. The limit of detection (LOD) and the limit of quantitation (LOQ) were 0.02 and 0.04 µg/ml, respectively. Coefficients of variation calculated for intr‐ aday and inter‐day precision were <2.53% and <1.29%, respectively.
For CPR, the assay of calibration standards was linear with a correlation coefficient of >0.9997. Plasma recovery ranged from
96.34% to 99.97%. The LOD and the LOQ were 0.02 and 0.04 µg/ ml, respectively. Coefficients of variation calculated for intraday and inter‐day precision were <3.88% and <2.17%, respectively.
For DNX, the assay of calibration standards was linear with a correlation coefficient of >0.9995. Plasma recovery ranged from 103.80% to 105.95%. The LOD and the LOQ were 0.02 and 0.04 µg/ ml, respectively. Coefficients of variation calculated for intraday and inter‐day precision were <2.33% and <1.55%, respectively.
2.5 | PK analysis
PK analyses were performed with Phoenix WinNonlin V 6.1.0.173 software (Pharsight, Certara). The PK parameters, including the area under the concentration–time curve (AUC), total plasma clearance (ClT), the volume of distribution at steady‐state (Vdss), the elimina‐ tion rate constant (λz), the terminal half‐life (t1/2λz), and the mean residence time (MRT) were calculated using the noncompartmental method. The maximum concentration (Cmax) and the time to reach maximum concentration (Tmax) were determined directly from the plasma concentration–time curve from each animal. The t1/2λz was calculated by ln 2/λz. The AUC was estimated by the log‐trapezoidal rule. Bioavailability (F) after IM administrations was calculated using the following formula:
Mean absorption time (MAT) was calculated by the following equation:
2.6 | PK‐PD analysis
PK‐PD analysis of ENR, DNX, and CPR (AUC0‐24/MIC90 and Cmax/ MIC90 values) was conducted using the PK parameters obtained in this study and the MIC90 values reported in previous studies in calves against E. coli (ENR ≤0.25 µg/ml, CPR ≤0.12 µg/ml, and DNX ≤0.50 µg/ml), P. multocida (ENR, CPR, and DNX ≤0.03 µg/ ml), and M. bovis (ENR ≤0.50 µg/ml, CPR ≤1 µg/ml, and DNX ≤0.50 µg/ml; Heuvelink, Reugebrink, & Mars, 2016; Lysnyansky & Ayling, 2016; Mevius, Breukink, & Miert, 1990; Portis, Lindeman, Johansen, & Stoltman, 2012; Sunderland et al., 2003). The MIC90 value is a commonly used PD parameter to determine the dosage regimen of antimicrobial drugs (Lees & Shojaee Aliabadi, 2002). For this reason, MIC90 values instead of MIC values were used in this study.
2.7 | Statistical analyses
Statistical analyses were performed using commercially available software (SPSS, 19.0 software; IBM). MRT and t1/2λz values are presented as harmonic means. Tmax is presented as a median value. Other PK parameters are expressed as the mean ± SD. A p value of
F =(AUCIM∕AUCIV) × 100.
<0.05 was considered statistically significant. Statistical significance was determined using the Mann–Whitney U test (nonparametric data, such as Tmax, MRT, and t1/2λz, AUC) or an independent t test (parametric data, such as ClT, Cmax, and ʎz; Powers, 1990).
3 | RESULTS
3.1 | PK analyses
The mean plasma concentration–time curves for ENR, CPR, and DNX in premature calves following IV and IM administration of ENR and DNX are shown in Figures 1 and 2, respectively. The PK param‐ eters obtained following IV and IM administration of ENR and DNX are presented in Table 1.
The t1/2λz and ClT of ENR following IV administration were 11.16 hr and 0.07 L hr−1 kg−1, respectively. The V
dss of ENR was 1.06 L/kg. The t1/2λz and MRT of ENR following IM administration were longer than those after IV administration (p < 0.05). The F value was 118% for ENR. The mean ratio of AUC0‐48CPR/AUC0‐48ENR for the ENR metabolite CPR was 0.20 and 0.16, after IV and IM administra‐ tion of ENR, respectively.
The t1/2λz and ClT of DNX following IV administration were 17.47 hr and 0.18 L hr‐1 kg−1, respectively. The t
1/2λz and MRT of DNX
administered IM were much longer than IV administration in prema‐ ture calves (p < 0.05). The F value for DNX after IM administration was 124%. The Vdss of DNX was 4.45 L/kg.
3.2 | PK‐PD analyses
The ratios of AUC0‐24/MIC90 and Cmax/MIC90 calculated using MIC90 values of ENR, CPR, and DNX against P. multocida, M. bovis, and
E. coli are presented in Table 2. According to MIC90 (≤0.03–0.5 µg/ ml) values for P. multocida, M. bovis, and E. coli, the AUC0‐24/MIC90 and Cmax/MIC90 ratios were considered to be optimal values for IV and IM administration of ENR in this study. In our study, consider‐ ing P. multocida with MIC90 values of ≤0.03 µg/ml, the Cmax/MIC90 and AUC0‐24/MIC90 values for DNX following IV and IM administra‐ tion were higher than the target ranges. However, the Cmax/MIC90 and AUC0‐24/MIC90 ratios for DNX were below the target ranges for
M. bovis and E. coli, with MIC90 values of ≤0.5 µg/ml.
4 | DISCUSSION
Numerous studies have determined the PK values of drugs in pre‐ mature infants in human medicine (Anderson, Allegaert, Anker,
F I G U R E 1 Mean (± SD) semi‐
logarithmic plasma concentration–time curves of ENR and ciprofloxacin (CPR) following single IV and IM administrations of ENR at dose of 10 mg/kg in premature calves (n = 6)
F I G U R E 2 Mean (± SD) plasma concentration–time curves following single IV and IM administrations of danofloxacin at dose of 8 mg/kg
Cossey, & Holford, 2007; Lo et al., 2010); however, no studies have been conducted to determine the PK properties of antimicrobial drugs in any premature animal species. Many studies have been performed to determine the PK profiles of ENR and DNX in calves. Previous studies have shown that ENR or DNX administered IV or IM to calves exhibit complete bioavailability (high F), large Vd, rapid Cl, and a long t1/2ʎz values (Daundkar et al., 2015; McKellar et al., 1999). However, it should be noted that the use of these PK pa‐ rameters can be misleading in premature calves since they repre‐ sent values in normal birth calves. Thus, we aimed (a) to investigate PK parameters of ENR or DNX and (b) to compare the PK values
acquired from this study with the PD values (MIC) obtained in pre‐ vious studies.
The mean Vdss of ENR after IV administration (1.06 L/kg) was smaller than that reported in one‐day‐old calves (1.81 L/kg) and one‐week calves (2.28 L/kg; Kaartinen et al., 1997). It can be said that ENR has a smaller Vdss in the newborn. The lower distribution of ENR was previously reported for 4‐ to 5‐month‐old calves (Davis et al., 2007). The Vdss value for DNX in premature calves (4.45 L/ kg) is higher than that previously reported in six‐month‐old calves (3.12 L/kg; Aliabadi & Lees, 2003); however, it is similar to that previously reported in 2‐ to 3‐week‐old calves (4.12 L/kg; Mzyk,
TA B L E 1 Mean (± SD) pharmacokinetic parameters of ENR (10 mg/kg, IV and IM administration), ciprofloxacin, and danofloxacin (8 mg/
kg, IV and IM administration) in premature calves (n = 6)
Parameter (units)
ENR Ciprofloxacin Danofloxacin
IV IM IV IM IV IM ʎz (1/hr) 0.06 ± 0.01 0.03 ± 0.01* 0.03 ± 0.01 0.01 ± 0.00* 0.04 ± 00 0.02 ± 0.00* t1/2ʎz (hr) (Harmonic mean) 11.16 ± 1.37 21.10 ± 4.62* 24.95 ± 3.81 47.01 ± 5.20* 17.47 ± 0.60 28.41 ± 0.89* ClT (L/hr/kg) 0.07 ± 0.00 — — — 0.18 ± 0.01 — Vdss (L/kg) 1.06 ± 0.11 — — — 4.45 ± 0.17 — Cmax (µg/ml) — 7.55 ± 0.48 1.05 ± 0.06 0.80 ± 0.02* — 2.15 ± 0.08 Tmax (hr) (Median) — 5.33 8.00 8.00 — 3.00 F (%) — 118 — — — 124 AUC0−24 (hr*µg/ml) 114.67 ± 6.80 113.67 ± 4.80 17.26 ± 1.11 14.86 ± 0.74 28.98 ± 1.02 31.95 ± 1.21 AUC0−48 (hr*µg/ml) 139.75 ± 7.33 164.34 ± 6.07* 27.24 ± 1.81 26.15 ± 1.45 38.90 ± 1.28 48.32 ± 1.03* MRT (hr) (Harmonic mean) 12.98 ± 0.43 18.04 ± 0.65* 38.28 ± 5.34 69.05 ± 7.94* 15.50 ± 0.20 18.83 ± 0.21* MAT (hr) — 5.06 — 30.77 — 3.33
AUC0‐48CPR/AUC0‐48ENR — — 0.20 ± 0.02 0.16 ± 0.01 — —
Abbreviations: ʎz, elimination rate constant; AUC, area under the concentration‐versus‐time curve; ClT, total clearance; Cmax, maximum plasma con‐
centration; F, bioavailability; IM, intramuscular; IV, intravenous; MAT, mean absorption time; MRT, mean residence time; t1/2ʎz, elimination half‐life;
Tmax, time to reach the maximum concentration; Vdss, volume of distribution at steady‐state.
*Significantly different from IV administration (p < 0.05).
Bacteria
ENR Ciprofloxacin Danofloxacin
IV IM IV IM IV IM Pasteurella multocida MIC90 (µg/ml) 0.03 0.03 0.03 AUC/MIC90 3,822 3,789 575 495 966 1,065 Cmax/MIC90 — 252 35 27 — 72 Mycoplasma bovis MIC90 (µg/ml) 0.5 1 0.5 AUC/MIC90 229 227 17 15 58 64 Cmax/MIC90 — 15 1 0.8 — 4 Escherichia coli MIC90 (µg/mL) 0.25 0.12 0.5 AUC/MIC90 459 455 144 124 58 64 Cmax/MIC90 — 30 9 7 — 4
Abbreviations: AUC, area under the concentration‐versus‐time curve; ENR, Enrofloxacin; IV, intra‐ venous; IM, intramuscular; MIC, minimum inhibitor concentration.
TA B L E 2 Surrogate markers of efficacy
from pharmacokinetics parameters obtained for ENR (10 mg/kg, IV and IM administration), ciprofloxacin, and danofloxacin (8 mg/kg, IV and IM administration)
Baynes, Messenger, Martinez, & Smith, 2017). The Vdss is affected by age‐related changes, such as the ratio of binding to plasma proteins, the body fat–water composition, hemodynamic parameters, and the physicochemical properties of the drugs (Mangoni & Jackson, 2004). Fluoroquinolones are lipid‐soluble antimicrobial agents and have a large Vdss in animals (Brown, 1996). The binding ratio of DNX to plasma proteins in premature calves was not determined in this study. However, the activity of protein binding of DNX has been re‐ ported as 36% in calves (Sappal, Chaudhary, Sandhu, & Sidhu, 2009). The total amount of plasma protein in human neonates is lower than that of adults, leading to an increase in the amount of free drug (Grandison & Boudinot, 2000). The large Vdss of DNX in premature calves may be due to the low plasma protein content and high extra‐ cellular fluid volume. In this study, Vdss of DNX (4.45 L/kg) was higher than Vdss of ENR (1.06 L/kg). In a study conducted in pneumonic calves, it was determined that the DNX concentration was more than five times more abundant in the lung tissue than in the plasma after IM administration (Apley & Upson, 1993). In previous studies, the higher tissue concentration of DNX than ENR with a larger Vdss has been reported in chickens (Knoll, Glünder, & Kietzmann, 1999). In addition, it has been demonstrated that the lung concentration of DNX is higher than the plasma concentration in previous studies (Apley & Upson, 1993). The higher Vdss of DNX compared with ENR in premature calves might indicate that DNX tends to accumulate in specific organs and shows a good penetration and wide distribution.
ENR is rapidly metabolized to the pharmacologically active me‐ tabolite CPR (Kaartinen et al., 1997). For this reason, the PK parame‐ ters of CPR were also determined in this study. The AUCCPR/AUCENR ratio is an indicator of the transformation of the parent drug ENR to the active metabolite CPR. In this study, the ratio of AUCCPR/AUCENR for ENR was 0.20 and 0.16 for IV and IM administration, respec‐ tively. The AUCCPR/AUCENR ratio of 0.69 after the SC administration of ENR has been reported for 4‐ to 5‐month‐old calves (Davis et al., 2007). Kaartinen et al. (1997) have revealed that the conversion of ENR to its metabolites takes longer in newborn calves than in older calves. ENR is metabolized to ciprofloxacin by the liver, and fluoroquinolone metabolism includes the cytochrome P450 system (Martinez et al., 2006). Furthermore, the cytochrome P450 enzyme activities in newborn calves dramatically increase within a week after birth (Shoaf, Schwark, Guard, & Babish, 1987). In this study, the slower metabolism of ENR to CPR in premature calves compared with that in full‐term calves may be related to the low activity of cytochrome P450.
The t1/2ʎz (11.16 hr) and ClT (0.07 L hr−1 kg−1) values of ENR after IV administration obtained in this study were longer and lower than those reported for one‐day‐old calves (t1/2ʎz of 6.61 hr and ClT 0.19 L hr−1 kg−1; Kaartinen et al., 1997). The plasma t
1/2ʎz (17.47 hr) and ClT (0.18 L hr−1 kg−1) values obtained following IV administration of DNX in our study were different from previously reported values in 6‐ to 8‐month‐old calves (t1/2ʎz of 4.24 hr and ClT of 0.71 L hr−1 kg−1; Sappal et al., 2009). The t1/2ʎz and ClT values determined in our study indicated that ENR and DNX were eliminated in premature calves more slowly than full‐term calves. Fluoroquinolones are eliminated by
renal and hepatic routes (Martinez et al., 2006). Drug elimination is in‐ fluenced by age‐related maturation of elimination organs (Mangoni & Jackson, 2004). The incomplete development of renal clearance and the immature metabolism of drugs are the primary factors leading to slower elimination (Nouws, 1992). Differences in developmental changes during the maturation of excretion mechanisms may cause a lower ClT and a longer t1/2λz of DNX and ENR in premature calves.
The t1/2λz does not usually vary with the route of administration (Toutain & Bousquet‐Mélou, 2004a). However, the t1/2λz and MRT values of ENR or DNX administered IM were much longer than those after IV administration in premature calves. Developmental differences in excretion mechanisms and use of a parallel PK design may have resulted in the longer t1/2λz and MRT of DNX and ENR in this study (Mangoni & Jackson, 2004; Toutain & Bousquet‐Mélou, 2004a). In addition to these, it is physiologically impossible to have an F value greater than 100% (Toutain & Bousquet‐Mélou, 2004b); however, the F values of ENR or DNX in this study was 118% and 124%, respectively, after IM injection. The use of different animal groups for IV and IM administration may have resulted in F values greater than 100% (Toutain & Bousquet‐Mélou, 2004b; Yáñez, Remsberg, Sayre, Forrest, & Neal, 2012). Use of the parallel PK de‐ sign and the incomplete development of organs involved in drug elimination in premature calves could have also contributed to the F values being greater than 100% following IM administration.
Premature calves remain susceptible to infections, in part due to their relative immunological incompetence and in part due to invasive techniques commonly used in veterinary environments. P. multocida,
M. bovis, and E. coli are the most prominent bacterial pathogens in
newborn calves (Fecteau, Smith, & George, 2009). In this study, the
Cmax/MIC and AUC0‐24/MIC ratios were calculated using the MIC90 values (0.03–1 µg/ml) reported for P. multocida, M. bovis, and E. coli (Heuvelink et al., 2016; Lysnyansky & Ayling, 2016; Mevius et al., 1990; Portis et al., 2012; Sunderland et al., 2003). The AUC0‐24/MIC ratio of >125 and the Cmax/MIC ratio of >10 were used as a thresh‐ old to achieve a successful therapeutic outcome for fluoroquino‐ lone against sensitive gram‐negative bacteria. Considering AUC0‐24/ MIC90 and Cmax/MIC90 ratios provided in this study, ENR following IV and IM administration at the dosage of 10 mg/kg can be effec‐ tive for treatment of sensitive bacterial infections with MIC90 values of ≤0.5 µg/ml. The AUC0‐24/MIC90 and Cmax/MIC90 ratios for DNX were above the suggested values against MIC90 values of ≤0.03 µg/ ml. Hence, IV and IM administration of DNX at a dose of 8 mg/kg could maintain effective plasma concentrations for the treatment of sensitive bacterial infections with MIC90 values of ≤0.03 µg/ml in premature calves. However, the AUC0‐24/MIC90 and Cmax/MIC90 ratios of DNX were below the suggested values for MIC90 values of ≤0.5 µg/ml. However, the AUC0‐24/MIC ratio of 50 is sufficient for fluoroquinolones in the treatment of gram‐positive bacteria (Papich, 2014). Thus, ENR or DNX may maintain serum concentrations of these drugs above the MIC90 up to 0.5 μg/ml for gram‐positive bac‐ terial infections in premature calves.
In conclusion, a PK study was performed for ENR and DNX, and the findings describe the premature birth‐related changes in drug
disposition in calves. Alterations in the PK of ENR and DNX in pre‐ mature calves are most probably related to the maturation of organs involved in the absorption, distribution, and elimination of these drugs. The use of PK parameters in conjunction with the PD param‐ eters provided an insight into the dosage regimen of ENR and DNX in premature calves. The integrated PK/PD analysis revealed that 10 mg/kg is an optimal dose for ENR in the treatment of susceptible bacterial infection with MIC values ≤0.5 mg/L in premature calves. Furthermore, the dose of 8 mg/kg for DNX could achieve the best efficacy against bacterial strains with a MIC value of 0.03 mg/L in premature calves. However, further study in naturally diseased pre‐ mature animals and disease models are required to validate these findings in a clinical situation. These results should allow better se‐ lection of the dose in any future clinical trials in premature animals.
ACKNOWLEDGMENTS
This research did not receive any specific grant from funding agen‐ cies in the public, commercial, or not‐for‐profit sectors. Abstract presented form at the 2nd International Congress on Advances in Veterinary Sciences & Technics, Skopje, Macedonia, October 2017.
CONFLIC T OF INTEREST
The authors declare no conflicts of interest.
AUTHOR CONTRIBUTIONS
OC, KU, and FA contributed to conception, design, analysis, and ac‐ quisition, drafted the manuscript, critically revised the manuscript, gave final approval, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. RY, MI, and MO contributed to experimental design and agreed to be accountable for all aspects of work ensuring integrity and accuracy. All authors have read and approved the final manuscript.
ORCID
Orhan Corum https://orcid.org/0000‐0003‐3168‐2510 Feray Altan https://orcid.org/0000‐0002‐9017‐763X Kamil Uney https://orcid.org/0000‐0002‐8674‐4873
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How to cite this article: Corum O, Altan F, Yildiz R, Ider M,
Ok M, Uney K. Pharmacokinetics of enrofloxacin and danofloxacin in premature calves. J vet Pharmacol Therap. 2019;42:624–631. https ://doi.org/10.1111/jvp.12787
