J vet Pharmacol Therap. 2019;42:497–504. wileyonlinelibrary.com/journal/jvp © 2019 John Wiley & Sons Ltd
|
4971 | INTRODUCTION
Ivermectin, a member of the macrocyclic lactone group, was ob‐ tained from the Streptococcus avermitilis cultures. It is one of the most effective and widely used antiparasitic agents because of its broad‐spectrum activity against numerous endo‐ and ectoparasites (McKellar & Gokbulut, 2012). Its mode of action involves the act on gamma‐aminobutyric acid (GABA) neurotransmission and glutamate
gate Cl−, thereby paralyzing pharyngeal and somatic muscles (Taylor,
2001). The drug is exceptionally safe for mammalians. However, ad‐ verse effects observed in some dog and cattle breeds (Collie and Australian shepherd dogs, Murray Grey cattle) are related to neuro‐ intoxication with GABA receptor stimulation, which was due to de‐ ficient of P‐glycoprotein (P‐gp) (Woodward, 2005). The first defense against orally ingested toxins and xenobiotics is the gastrointestinal tract which contains cells that express high levels of P‐gp, and P‐gp
Received: 13 February 2019
|
Revised: 22 March 2019|
Accepted: 25 March 2019 DOI: 10.1111/jvp.12769P H A R M A C O K I N E T I C R E P O R T
Investigation of pharmacokinetic interaction between
ivermectin and praziquantel after oral administration in healthy
dogs
Zeynep Ozdemir
1| Hatice Eser Faki
2| Kamil Uney
2| Bunyamin Tras
21Anatolia Medicine & Chemical Industry Corporation, Konya, Turkey
2Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Selcuk, Konya, Turkey
Correspondence
Zeynep Ozdemir, Anatolia Medicine & Chemical Industry Corporation, Konya, Turkey.
Email: zynp.ozdmr@windowslive.com
Abstract
The purpose of this study was to determine the pharmacokinetic interaction be‐ tween ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) administered either alone or co‐administered to dogs after oral treatment. Twelve healthy cross‐bred dogs (weighing 18–21 kg, aged 1–3 years) were allocated randomly into two groups of six dogs (four females, two males) each. In first group, the tablet forms of praziquantel and ivermectin were administered using a crossover design with a 15‐day washout period, respectively. Second group received tablet form of ivermectin plus praziquan‐ tel. The plasma concentrations of ivermectin and praziquantel were determined by high‐performance liquid chromatography using a fluorescence and ultraviolet detec‐ tor, respectively. The pharmacokinetic parameters of ivermectin following oral alone‐ administration were as follows: elimination half‐life (t1/2λz) 110 ± 11.06 hr, area under the plasma concentration–time curve (AUC0–∞) 7,805 ± 1,768 hr.ng/ml, maximum concentration (Cmax) 137 ± 48.09 ng/ml, and time to reach Cmax (Tmax) 14.0 ± 4.90 hr. The pharmacokinetic parameters of praziquantel following oral alone‐administration were as follows: t1/2λz 7.39 ± 3.86 hr, AUC0–∞ 4,301 ± 1,253 hr.ng/ml, C
max 897 ± 245 ng/ml, and Tmax 5.33 ± 0.82 hr. The pharmacokinetics of ivermectin and praziquantel were not changed, except Tmax of praziquantel in the combined group. In conclusion, the combined formulation of ivermectin and praziquantel can be pre‐ ferred in the treatment and prevention of diseases caused by susceptible parasites in dogs because no pharmacokinetic interaction was determined between them.
K E Y W O R D S
plays a critical role in pharmacokinetics and toxicokinetics (Chan, Lowes, & Hirst, 2004; Szakacs, Varadi, Ozvegy‐Laczka, & Sarkadi, 2008). P‐gp plays an important role on transport and distribution of ivermectin, which is a P‐gp substrate (Kim, 2002; Kwei et al., 1999; Pouliot, L'Heureux, Liu, Prichard, & Georges, 1997).
Praziquantel is a pyrazinoisoquinoline used against various cestode and trematode parasites, most notably schistosomes for veterinary and human medicine (Dayan, 2003). Its anthelmintic efficacy is based on muscle contraction and tegument damage, which arises from an in‐ creased influx of divalent calcium ions, followed by spastic paralysis. This paralysis and tegument disintegration cause temporarily lose their parasitic locations in flatworms (Andrews, 1985). Drug transporter specificity has not been conclusively characterized for praziquantel (Hayeshi, Masimirembwa, Mukanganyama, & Ungell, 2006). However, it is known that praziquantel is metabolized by cytochrome P450 (CYP) isoenzymes like CYP1A2, CYP2B1, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 (Kigen & Edwards, 2017; Li, Björkman, Andersson, Gustafsson, & Masimirembwa, 2003). P‐gp‐mediated absorption and excretion can be coordinately regulated with CYP family and glutathi‐ one‐S‐transferases in the liver and small intestine (Gatmaitan & Arias, 1993). Especially, CYP3A4 is likely to play a synergistic role with P‐gp in regulating the bioavailability of many orally ingested compounds (Chan et al., 2004). Additionally, a substantial overlap in substrate specificity exists between CYPs and P‐gp (Wacher, Wu, & Benet, 1995).
Plasma pharmacokinetics of ivermectin (Gokbulut, Karademir, & Boyacioglu, 2007; Gokbulut et al., 2010; Lanusse et al., 1997; Magalhães et al., 2016; Mestorino, Turic, Pesoa, Echeverría, & Errecalde, 2003) and praziquantel (Giorgi et al., 2003; Hong et al., 2003; Qian, Wei, Hao, & Tang, 2017; Sun & Bu, 2012) have been determined for different administration routes in some species. Although there are several commercial products combining the two drugs together for dogs, no data on the combination pharmacoki‐ netics of ivermectin and praziquantel in dogs following oral admin‐ istration were reported. However, pharmacokinetics of ivermectin plus praziquantel combination have been reported after intramus‐ cular administration in sheep and pigs (Tang, Chen, Qian, Hao, & Xiao, 2016; Tang et al., 2012). In dogs, the determination of orally co‐administered ivermectin and praziquantel pharmacokinetics can provide many benefits in practice (a) to minimize the pain and dis‐ comfort caused by the parenteral injection, (b) to provide facileness in drug administration, and (c) to treat and prevent most internal–ex‐ ternal parasite infestation by a single drug administration.
The aim of this study was to determine whether there is a phar‐ macokinetic interaction for oral administration between ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg), which are widely used in veterinary practice.
2 | MATERIALS AND METHODS
2.1 | Chemicals
Ivermectin (>89.3%) and praziquantel (>99.1%) powders were sup‐ plied from Anatolia Medicine & Chemical Industry Corporation.
Acetonitrile and methanol were used at appropriate purities for high‐performance liquid chromatography (HPLC) and were supplied from VWR (Fontenay‐sous‐Bois). Orthophosphoric acid, 1‐meth‐ ylimidazole, trifluoroacetic anhydride were supplied from Sigma‐ Aldrich. Potassium dihydrogen phosphate was provided from Merck.
2.2 | Animals
A total of 12 cross‐bred healthy dogs (eight females, four males), 1–3 years old and weighing 18–21 kg were used in the study. The dogs were individually allocated in cages and were fed once daily with adult dog food and ad libitum water during the study. They did not receive any other medications for at least 2 months prior to the beginning of this study. The animals were observed for drug side effects (emesis, salivation, diarrhea, weakness, anorexia etc.) dur‐ ing 24 hr in the praziquantel group and 21 days in the ivermectin and combined group. The dogs used in the study are experimen‐ tal animals, which belong to a research farm (Faculty of Veterinary Medicine, Selcuk University, Turkey). The Ethics Committee of the Selcuk University, Faculty of Veterinary Medicine (no. 2018/50) ap‐ proved all study protocols for dogs.
2.3 | Experimental design
The dogs were selected randomly and allocated into two groups of six dogs (four females, two males) each. Before 1 hr from the treat‐ ment, the dogs were fed. Then, dogs received drugs with a piece of sausages. In the first group, the study was performed using crosso‐ ver design. The tablet form of praziquantel (Niklovet Fort, 250 mg praziquantel, VETAS) was administered orally at a single dose of 10 mg/kg (Casaravilla et al., 2005). Heparinized blood samples (2 ml) were collected prior to drug administration (0) and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18, and 24 hr after drug administration. After a 15‐day washout period, ivermectin tablet form (Damla‐Ilac, 10 mg ivermectin) was administered to the same dogs orally at a single dose of 0.4 mg/kg (Medleau, Iistic & McElveen, 1996). There is no com‐ mercial formulation of the ivermectin tablet form in Turkey, so it was produced as a special prototype for this study. Heparinized blood samples (2 ml) were collected prior to drug administration (0) and at 1, 3, 6, 12 hr and 1, 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, and 21 days after drug administration.
Dogs in the second group received orally the tablet form of ivermectin (0.4 mg/kg) and praziquantel (10 mg/kg) combina‐ tion (Dicromec, 250 mg praziquantel, 10 mg ivermectin, Anatolia Medicine & Chemical Industry Co.) at a single dose. Heparinized blood samples (2 ml) were collected prior to drug administration (0) and at 0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 18 hr and 1, 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, and 21 days after drug administration.
Intravenous catheters were placed into V.cephalica antebrachii for collection of blood samples during 24 hr. The blood samples at other time points were collected by venipuncture. All the blood samples were centrifuged at 2,000 g for 10 min within 1 hr after collection. Plasma samples were stored at −80°C and analyzed within 2 months.
2.4 | Analytical procedure
The plasma concentrations of praziquantel and ivermectin were determined using a HPLC system (Shimadzu) consisting of a pump (LC‐20AT), a degasser (DGU‐20A 5R) to pump the mobile phase, an autosampler (SIL 20A), and a column oven (CTO 10AS VP). Chromatographic separation for ivermectin and praziquantel was performed using a reversed‐phase column (Gemini C18 column, 250 mm × 4.6 mm i.d., 5 μm; Phenomenex).
2.4.1 | Ivermectin
Plasma concentration of ivermectin was analyzed by HPLC using the modified method reported by Magalhães et al. (2016). A fluores‐ cence detector (RF‐20A XS, Shimadzu, Japan), which set at an excita‐ tion wavelength of 365 nm and an emission wavelength of 475 nm, was used to detect ivermectin. The column and autosampler were kept at room temperature. The mobile phase consisted of methanol and water (97:3, v/v). The flow rate was 1 ml/min and the injection volume was 10 μl.
The plasma samples (100 μl) were mixed with 100 μl acetonitrile. After centrifugation at 11,000 g for 10 min, 80 μl supernatant was dried under a gentle stream of nitrogen at 50°C in a water bath. The dry residue was dissolved in 30 μl of 1‐methylimidazole solution in acetoni‐ trile (1:1, v/v). To initiate the derivatization, 50 μl trifluoroacetic anhy‐ dride solution in acetonitrile (1:1, v/v) was added and vortexed for 30 s. Then, all of the mixture was transferred to HPLC autosampler vials.
The calibration standard curves of ivermectin prepared using blank plasma were linear between 2.5–400 ng/ml (r2> 0.9997). The
limit of detection (LOD) and limit of quantification (LOQ) of ivermec‐ tin in plasma were 1.25 and 2.5 ng/ml, respectively. Ivermectin qual‐ ity control (QC) samples at low (4 ng/ml), medium (40 ng/ml), and high (400 ng/ml) concentrations were prepared in plasma for deter‐ mining the recovery, precision, and accuracy in three replicates for six consecutive days. The precision of the method was presented as the percent coefficient of variation (CV %), and the accuracy was determined by calculating the percent bias from the theoretical con‐ centration. The analytical recovery for ivermectin in plasma was >89%. The intra‐ and inter‐day CV were <5% and <9%, respectively. The intra‐ and inter‐day bias ranged from −5.6% to 1.4% and from −3.6% to 1.6%, respectively.
2.4.2 | Praziquantel
Plasma concentration of praziquantel was analyzed by HPLC using the modified methods reported by Kim, Kim, and Kim (2001) and Morovján, Csokán, Makranszki, Abdellah‐Nagy, and Tóth (1998). The detection of praziquantel in plasma was performed using a SPD‐10A UV‐VIS detector set at 210 nm. The column and autosampler were kept at room temperature. The mobile phase consisted of acetoni‐ trile and 0.05 M potassium dihydrogen phosphate (55:45, v/v) so‐ lution. The pH of buffer was adjusted to 3.0 with orthophosphoric acid. The flow rate was 1 ml/min, and the injection volume was 10 μl.
The plasma samples (200 μl) were mixed with 200 μl acetonitrile. After centrifugation at 11,000 g for 10 min, 200 μl supernatant was dried under a gentle stream of nitrogen at 50°C in a water bath. The dry residue was dissolved in 100 μl of 10% acetonitrile in water, and all of the mixture was transferred to HPLC autosampler vials.
The calibration standard curves of praziquantel prepared using blank plasma were linear between 20 and 4,000 ng/ml (r2 > 0.9999).
The LOD and LOQ of praziquantel in plasma were 10 and 20 ng/ ml, respectively. Praziquantel QC samples at low (40 ng/ml), medium (400 ng/ml), and high (4,000 ng/ml) concentrations were prepared in plasma for determining the recovery, precision, and accuracy in three replicates for six consecutive days. The analytical recovery for praziquantel in plasma was >88%. The intra‐ and inter‐day CV were <2% and <7%, respectively. The intra‐ and inter‐day bias ranged from −1.25% to 2.8% and from −0.68% to 0.05%, respectively.
2.5 | Pharmacokinetic calculations
The plasma concentrations of ivermectin and praziquantel in each animal were analyzed by noncompartmental method using the WinNonLin 6.2 software program (Pharsight Corporation). The area under the curve (AUC) was calculated using the linear/log method. The elimination rate constant (λz) was determined using linear re‐ gression analysis from the linear part of the terminal phase. The terminal half‐life (t1/2λz) was estimated by ln(2)/λz. The maximum concentration (Cmax) and time to reach Cmax (Tmax) following oral ad‐ ministration of ivermectin and praziquantel were determined from observed data on the plasma concentration–time curve. The AUC extrapolated was calculated to evaluate the importance of measur‐ ing the last concentration and using the following equation: AUC ex‐ trapolated (%): (AUC∞−AUCt)/AUC∞ × 100.
2.6 | Statistical analysis
The pharmacokinetic parameters are reported as mean ± SD. Harmonic means were calculated for t1/2λz and MRT0‐∞, which were compared using Mann–Whitney U test. Other pharmacokinetic parameters were statistically compared for statistical significance using the independent t test. A value of p < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS 23.0 statistical software (IBM).
3 | RESULTS
Clinically, any adverse drug effects related to ivermectin and prazi‐ quantel in dogs were not observed during the trials. The plasma concentration–time curves and the pharmacokinetic parameters after the oral administration of ivermectin either alone or co‐ad‐ ministered with praziquantel are shown in Figure 1 and Table 1, re‐ spectively. After the oral administration, ivermectin was determined in plasma during 15 days. Praziquantel did not change the plasma disposition of ivermectin after the oral administration. The plasma
concentration–time curves and the pharmacokinetic parameters after the oral administration of praziquantel either alone or co‐ad‐ ministered with ivermectin are shown Figure 2 and Table 2, respec‐ tively. The Tmax was significantly longer in praziquantel group than praziquantel plus ivermectin treatment (p < 0.05). No statistical differences between both treatments were observed for the other pharmacokinetic parameters. The pharmacokinetics of ivermectin and praziquantel showed no gender‐related differences. The per‐ centage AUC extrapolated values for all treatment groups were less than 20%.
4 | DISCUSSION
The drugs are combined in same pharmaceutic form for purposes such as improving clinical effectiveness and expanding the effect spectrum. In order to make these combinations, pharmacokinetic and pharmacodynamic interactions between drugs should be deter‐ mined for each animal species and breed.
In the ivermectin group, AUC0‐∞ and Cmax were 7805 hr.ng/ml
and 137 ng/ml, respectively. When AUC and Cmax values were nor‐ malized to same dose, our parameters were similar to previously reported values in Beagle dogs at different doses (0.069–0.3 mg/ kg) (Al‐Azzam, Fleckenstein, Cheng, Dzimianski, & McCall, 2007; Dunn et al., 2011; Walther, Allan, & Roepke, 2015), but lower than in cross‐bred dogs at 0.2 mg/kg dose (Gokbulut, Karademir, Boyacioglu, & McKellar, 2006) and in Beagle dogs at 0.6 mg/kg dose (Magalhães et al., 2016) after oral administration. Significant differ‐ ences of the AUC in these studies may be related to the affinity to fatty tissues due to high lipophilicity of ivermectin, P‐pg transport
F I G U R E 1 Comparative mean (± SD) plasma concentration
profiles for ivermectin (IVM) obtained after its administration (0.4 mg/kg) either alone or co‐administered with praziquantel (PZQ, 10 mg/kg) both given by the oral route to dogs (n = 6)
TA B L E 1 Plasma pharmacokinetic parameters obtained after the
oral administration of ivermectin (0.4 mg/kg) to dogs either alone or co‐administered with praziquantel (10 mg/kg) (mean ± SD, n = 6)b
Parameter Ivermectin (alone)
Ivermectin plus praziquantel λz (1/hr) 0.006 ± 0.001 0.007 ± 0.003 t1/2λza (hr) 110 ± 11.06 100 ± 39.52 AUC0‐∞ (hr.ng/ml) 7,805 ± 1,768 8,529 ± 2,920 AUC extrapolated (%) 6.41 ± 2.88 7.21 ± 4.56 Cmax (ng/ml) 137 ± 48.09 140 ± 55.66 Tmax (hr) 14.0 ± 4.90 16.0 ± 9.03 Vz/F (ml/kg) 8,819 ± 3,381 8,860 ± 5,340 Cl/F (ml/hr.kg) 54.45 ± 17.24 52.61 ± 21.07 MRT0‐∞a (hr) 101 ± 26.71 111 ± 35.31
Note. Abbreviations: AUC0‐∞: area under concentration–time curve from time 0 to infinity; AUC extrapolated %: area under the plasma concentration–time curve extrapolated from tlast to ∞ in of the total
AUC; Cmax: maximum concentration; Cl/F: apparent total clearance of
the drug from plasma after oral administration; λz: elimination rate constant; MRT0‐∞: mean residence time from time 0 to infinity; t1/2λz:
terminal half‐life, Tmax: time to reach maximum concentration; Vz/F:
apparent volume of distribution during terminal phase after oral administration.
aHarmonic mean. bThe kinetic parameter of ivermectin group is not
different from the ivermectin plus praziquantel group (p > 0.05).
F I G U R E 2 Comparative mean (± SD) plasma concentration
profiles for praziquantel (PZQ) obtained after its administration (10 mg/kg) either alone or co‐administered with ivermectin (IVM, 0.4 mg/kg) both given by the oral route to dogs (n = 6)
TA B L E 2 Plasma pharmacokinetic parameters obtained after the
oral administration of praziquantel (10 mg/kg) to dogs either alone or co‐administered with ivermectin (0.4 mg/kg) (mean ± SD, n = 6)
Parameter Praziquantel (alone)
Praziquantel plus ivermectin λz (1/hr) 0.094 ± 0.036 0.090 ± 0.038 t1/2λza (hr) 7.39 ± 3.86 7.73 ± 4.85 AUC0‐∞ (hr.ng/ml) 4,301 ± 1,253 2,914 ± 689 AUC extrapolated (%) 8.15 ± 4.58 10.45 ± 5.68 Cmax (ng/ml) 897 ± 245 587 ± 242 Tmax (hr) 5.33 ± 0.82 3.8 ± 0.45b Vz/F (ml/kg) 31,106 ± 16,518 48,457 ± 27,875 Cl/F (ml/hr.kg) 2,529 ± 881 3,591 ± 859 MRT0‐∞a (hr) 9.05 ± 1.89 9.29 ± 2.54
Note. aHarmonic mean. bThe kinetic parameter of ivermectin plus
praziquantel group is significantly different (p < 0.05) from the praziquantel group.
activity, and entering the enterohepatic circulation (Canga et al., 2009; Hennessy & Alvinerie, 2002). The low body fat percentage in dogs (e.g., Greyhound) can lead to a lower than expected volume of distribution for lipophilic compounds. This lower percent body fat can result in higher serum drug concentrations as compared to that seen in breeds with a higher percent body fat (Zoran, Riedesel, & Dyer, 1993). Breed‐related differences could cause dissimilarities in gastrointestinal transit time, intestinal fermentation, and drug dis‐ position (Fleischer, Sharkey, Mealey, Ostrander, & Martinez, 2008). It has been reported that the long transition time causes prolonga‐ tion in both gastric emptying time and small intestine transit time between breeds (Weber et al., 2002). Furthermore, ABCB1 gene polymorphism between dog breeds may affect the pharmacokinet‐ ics of ivermectin. Mealey and Meurs (2008) have reported a rela‐ tively high percentage of mixed‐breed dogs with the ABCB1 mut/ mut (7/238 [3%]) or ABCB1 mut/wt (19/238 [8%]) genotype. The
Tmax and t1/2λz (14.0 and 110 hr, respectively) were determined con‐ siderably longer in our study than previously reported values in dogs for ivermectin (Al‐Azzam et al., 2007; Dunn et al., 2011; Gokbulut et al., 2006; Magalhães et al., 2016; Walther et al., 2015). This can be explained by the formulation of ivermectin. In previous studies, since the injectable form is administered orally, the rate and degree of absorption of these formulations may vary according to the tablet. Furthermore, the hardness and friability of the tablets also affect the dissolution. Also, different Tmax values may be related to differ‐ ences in feeding time (Paulson et al., 2001; Walther et al., 2015). Studies in different animal species have shown that feeding time may alter the pharmacokinetics of anthelmintic drugs. Ivermectin probably binds onto digestate following oral administration just after feeding, and food withdrawal is likely to improve drug absorption (Marriner, McKinnon, & Bogan, 1987). Fasting or feed withdrawal before treatment could be useful for improving the anthelmintic efficacy in animals (Alvinerie, Sutra, Cabezas, Rubilar, & Perez, 2000). It has been shown that the pharmacokinetics of ivermectin is affected by the formulation (Lo, Fink, Williams, & Blodinger, 1985; Maeda, Brandon, & Sano, 2003) and administration route (Gokbulut et al., 2006; Imperiale, Lifschitz, Sallovitz, Virkel, & Lanusse, 2004; Perez et al., 2003). For oral administration of ivermectin at 0.4 mg/ kg dose, the Cmax (68.5 ng/ml) was found higher and closer, respec‐ tively (35.131 ng/ml and 66.80 ng/ml, respectively) than normalized values to 0.2 mg/kg dose in dogs following subcutaneous injections (Eraslan et al., 2010; Gokbulut et al., 2006). In contrast to subcuta‐ neous injection, oral administration of ivermectin provided a sig‐ nificantly higher plasma concentration. When the pharmacokinetic behavior of ivermectin is evaluated, it can be stated to use orally for the control and treatment of parasitic diseases in dogs.
In our study, AUC0‐∞ and Cmax (4301 hr.ng/ml and 897 ng/ml, re‐
spectively) in the praziquantel group were significantly lower than those normalized to a 10 mg/kg dose (AUC; 42300‐55088 hr.ng/
ml, Cmax; 3301‐8900 ng/ml) following oral administration of prazi‐
quantel tablet form at 30 mg/kg in Beagle dogs (Giorgi et al., 2003; Hong et al., 2003). The AUC and Cmax of praziquantel exhibited re‐ markable differences among dogs in the current study. Also, these
variations have been observed with praziquantel studies in humans (Andrews, Thomas, Pohlke, & Seubert, 1983; Mandour et al., 1990). Variations in dogs may be more common because the length of the duodenum, jejunum, and ileum, which affect drug absorption, is pos‐ itively correlated with canine body size (Albors et al., 2011). It was stated that factors such as the age, breed, and diet in dogs affected gastric emptying time, small intestinal emptying time, large intestine transit time, and intestinal flora in dogs (Martinez & Papich, 2009; Oswald, Sharkey, Pade, & Martinez, 2015; Rastall, 2004; Weber et al., 2001). Each and/or all of these can lead to the observation of pharmacokinetic differences between individuals. The Tmax obtained from our study (5.33 hr) was longer compared to other studies (0.75 and 2.25 hr, respectively) (Giorgi et al., 2003; Hong et al., 2003). The pharmaceutical formulation of praziquantel was an oral suspension in the study by Giorgi et al. (2003), but in the present study and the study by Hong et al. (2003) were tablet formulations. It can be said that the hardness and friability of tablets and the different phar‐ maceutical formulation can affect the Tmax of praziquantel. Five of canine CYP isoenzymes (CYP1A2, CYP2C41, CYP2D15, CYP2E1, and CYP3A12) have been reported to be genetically polymorphic. CYP1A2 plays a role in praziquantel metabolism (Li et al., 2003). Kamimura (2006) indicated that about 10%–15% of Beagle dogs may be CYP1A2‐deficient. These polymorphisms can lead to differ‐ ences in drug exposure and could result in breed‐related differences in drug response. Also, the differences in drug response may affect the safety and/or effectiveness of the drug (Fleischer et al., 2008; Kamimura, 2006). The Tmax (5.33 hr) determined in the praziquan‐ tel group was longer than the sustained‐release praziquantel tablet (3.2 hr) (Hong et al., 2003). The prolonged absorption of the drug may provide an advantage in efficacy as it will increase the expo‐ sure time of the drug to parasites (Jung, Medina, Castro, Corona, & Sotelo, 1997).
The usage of anthelmintic combinations, which have different acting mechanism, is reduced treatment time and provides broader action spectrum (Anderson, Martin, & Jarrett, 1988; Barnes, Dobson, & Barger, 1995). The co‐administration of drugs may induce changes in the pharmacokinetic behavior of either molecule. Studies have been carried out to determine the interaction between ecto/ endoparasitic drugs and ivermectin for oral administration in dogs. It was determined that spinosad and pyrantel pamoate changed iver‐ mectin plasma pharmacokinetic but fluralaner did not (Clark, Daurio, Skelly, Cheung, & Jeffcoat, 1992; Dunn et al., 2011; Walther et al., 2015). In the current research, no statistically (p > 0.05) significant pharmacokinetic changes were observed for ivermectin after its oral co‐administration with praziquantel in dogs. Only, Tmax was sig‐ nificantly longer in the praziquantel group (5.33 ± 0.82 hr) than the combined group (3.8 ± 0.45 hr). This difference may be related to dif‐ ferent tablet forms of praziquantel and experimental design. Tablets formulated by different pharmaceutical companies can show differ‐ ent hardness and friability. These properties of tablets can affect absorption (Seitz & Flessland, 1965). On the other hand, the AUC0‐∞ of praziquantel decreased more than 30% in the praziquantel plus ivermectin group compared to the praziquantel group; this decrease
has no significant statistically (p > 0.05) because of wide variation between dogs. Decrease in the AUC0‐∞ value of praziquantel in the praziquantel plus ivermectin group can be related to CYP3A4 enzyme induction, because it has been shown that ivermectin can be an inducer of several cytochrome P450 isoenzymes, including CYP1A, 2B, and 3A subfamilies (Skalova et al., 2001). Similarly to our results in conducted studies on ivermectin, praziquantel, and iver‐ mectin plus praziquantel‐administered sheep and pigs, no difference between pharmacokinetic parameters of ivermectin and ivermectin plus praziquantel group has been found. On the other hand, com‐ pared the combined and praziquantel groups, Tmax was found to be short significantly in sheep while no change observed in pigs (Tang et al., 2012, 2016). No interaction following the concomitant use of praziquantel, ivermectin, and albendazole has been reported in hu‐ mans (Na‐Bangchang et al., 2006).
The present study indicated that oral tablet form of ivermectin and praziquantel did not cause any detectable clinically adverse ef‐ fects in dogs. However, in terms of clinical efficacy, lower doses than 0.4 mg/kg may be preferred in dog breeds that are susceptible to ivermectin. The plasma pharmacokinetics except Tmax (praziquantel group) of both antiparasitic drugs was not influenced by their co‐ administration. In conclusion, the combined form of ivermectin and praziquantel can be preferred in the treatment and prevention of diseases caused by susceptible parasites in dogs.
ACKNOWLEDGMENTS
The abstract of this article was presented as an oral presentation at the congress “International Hippocrates Congress on Medical and Health Sciences, 1‐3 March 2019, Ankara, Turkey”.
CONFLIC T OF INTEREST
The authors declare that they have no conflict of interest.
AUTHOR CONTRIBUTIONS
Zeynep Ozdemir contributed to the conception, design, experimen‐ tal administration, analysis, drafted the manuscript, critically revised the manuscript, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Hatice Eser Faki contributed to the experimental process and analysis, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Kamil Uney contributed to the analysis, critically revised the manuscript, and agreed to be accountable for all aspects of work ensuring integrity and accuracy. Bunyamin Tras critically revised the manuscript and agreed to be accountable for all aspects of work ensuring integrity and accuracy.
ORCID
Zeynep Ozdemir https://orcid.org/0000‐0002‐3245‐7975
Kamil Uney https://orcid.org/0000‐0002‐8674‐4873
REFERENCES
Al‐Azzam, S. I., Fleckenstein, L., Cheng, K. J., Dzimianski, M. T., & McCall, J. W. (2007). Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogs. Biopharmaceutics
& Drug Disposition, 28(8), 431–438. https://doi.org/10.1002/
(ISSN)1099‐081X
Albors, O. L., Rojo, D., Sarriá, R., Soria, F., Cuadrado, E. P., & Latorre, R. (2011). Morphometry of the canine intestine with reference to the use of double balloon endoscopy. The Veterinary Journal, 190(1), 113– 118. https://doi.org/10.1016/j.tvjl.2010.08.017
Alvinerie, M., Sutra, J. F., Cabezas, I., Rubilar, L., & Perez, R. (2000). Enhanced plasma availability of moxidectin in fasted horses. Journal
of Equine Veterinary Science, 20(9), 575–578. https://doi.org/10.1016/
S0737‐0806(00)70265‐6
Anderson, N., Martin, P., & Jarrett, R. (1988). Mixtures of anthelmint‐ ics: A strategy against resistance. Australian Veterinary Journal, 65(2), 62–64. https://doi.org/10.1111/j.1751‐0813.1988.tb07355.x Andrews, P. (1985). Praziquantel: Mechanisms of anti‐schistosomal ac‐
tivity. Pharmacology & Therapeutics, 29(1), 129–156. https://doi. org/10.1016/0163‐7258(85)90020‐8
Andrews, P., Thomas, H., Pohlke, R., & Seubert, J. (1983). Praziquantel.
Medicinal Research Reviews, 3(2), 147–200. https://doi.org/10.1002/
(ISSN)1098‐1128
Barnes, E., Dobson, R., & Barger, I. (1995). Worm control and anthelmintic resistance: Adventures with a model. Parasitology Today (Personal
ed.), 11(2), 56–63. https://doi.org/10.1016/0169‐4758(95)80117‐0
Canga, A. G., Prieto, A. M. S., Liébana, M. J. D., Martínez, N. F., Vega, M. S., & Vieitez, J. J. G. (2009). The pharmacokinetics and metabolism of ivermectin in domestic animal species. The Veterinary Journal, 179(1), 25–37. https://doi.org/10.1016/j.tvjl.2007.07.011
Casaravilla, C., Malgor, R., Rossi, A., Sakai, H., Nonaka, N., Kamiya, M., & Carmona, C. (2005). Production and characterization of monoclonal antibodies against excretory/secretory products of adult Echinococcus granulosus, and their application to coproanti‐ gen detection. Parasitology International, 54(1), 43–49. https://doi. org/10.1016/j.parint.2004.08.006
Chan, L. M., Lowes, S., & Hirst, B. H. (2004). The ABCs of drug trans‐ port in intestine and liver: Efflux proteins limiting drug absorption and bioavailability. European Journal of Pharmaceutical Sciences, 21(1), 25–51. https://doi.org/10.1016/j.ejps.2003.07.003
Clark, J., Daurio, C., Skelly, B., Cheung, E., & Jeffcoat, A. (1992). Pharmacokinetics of [3H]‐ivermectin in the dog following oral ad‐ ministration of a beef‐based chewable formulation containing iver‐ mectin alone or in combination with pyrantel pamoate. Journal of
Veterinary Pharmacology and Therapeutics, 15(2), 217–220. https://
doi.org/10.1111/j.1365‐2885.1992.tb01009.x
Dayan, A. (2003) Albendazole, mebendazole and praziquantel. Review of non‐clinical toxicity and pharmacokinetics. Acta Tropica, 86(2‐3), 141–159. https://doi.org/10.1016/S0001‐706X(03)00031‐7 Dunn, S., Hedges, L., Sampson, K., Lai, Y., Mahabir, S., Balogh, L., &
Locuson, C. W. (2011). Pharmacokinetic interaction of the anti‐ parasitic agents ivermectin and spinosad in dogs. Drug Metabolism
and Disposition, 39(5), 789–795. https://doi.org/10.1124/
dmd.110.034827
Eraslan, G., Kanbur, M., Liman, B. C., Cam, Y., Karabacak, M., & Altinordulu, S. (2010). Comparative pharmacokinetics of some injectable preparations containing ivermectin in dogs. Food
and Chemical Toxicology, 48(8–9), 2181–2185. https://doi.
Fleischer, S., Sharkey, M., Mealey, K., Ostrander, E. A., & Martinez, M. (2008). Pharmacogenetic and metabolic differences between dog breeds: Their impact on canine medicine and the use of the dog as a preclinical animal model. The AAPS Journal, 10(1), 110–119. https:// doi.org/10.1208/s12248‐008‐9011‐1
Gatmaitan, Z. C., & Arias, I. M. (1993). Structure and function of P‐glyco‐ protein in normal liver and small intestine. Advances in Pharmacology,
24, 77–97. https://doi.org/10.1016/S1054‐3589(08)60934‐5
Giorgi, M., Meucci, V., Vaccaro, E., Mengozzi, G., Giusiani, M., & Soldani, G. (2003). Effects of liquid and freeze‐dried grapefruit juice on the pharmacokinetics of praziquantel and its metabolite 4_‐hydroxy praziquantel in beagle dogs. Pharmacological Research, 47, 87–92. https://doi.org/10.1016/S1043‐6618(02)00251‐7
Gokbulut, C., Cirak, V. Y., Senlik, B., Aksit, D., Durmaz, M., & McKellar, Q. A. (2010). Comparative plasma disposition, bioavailability and efficacy of ivermectin following oral and pour‐on administrations in horses. Veterinary Parasitology, 170(1–2), 120–126. https://doi. org/10.1016/j.vetpar.2010.01.041
Gokbulut, C., Karademir, U., & Boyacioglu, M. (2007). Comparison of plasma pharmacokinetic profile of ivermectin following administra‐ tion of subcutaneous injection (Baymec) and oral tablet (Efektin) in goats. Journal of Veterinary Pharmacology and Therapeutics, 30(5), 489–491. https://doi.org/10.1111/j.1365‐2885.2007.00888.x Gokbulut, C., Karademir, U., Boyacioglu, M., & McKellar, Q. A. (2006).
Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs. Veterinary
Parasitology, 135(3–4), 347–354. https://doi.org/10.1016/j.
vetpar.2005.10.002
Hayeshi, R., Masimirembwa, C., Mukanganyama, S., & Ungell, A. L. (2006). The potential inhibitory effect of antiparasitic drugs and nat‐ ural products on P‐glycoprotein mediated efflux. European Journal
of Pharmaceutical Sciences, 29(1), 70–81. https://doi.org/10.1016/j.
ejps.2006.05.009
Hennessy, D., & Alvinerie, M. (2002). In J. Vercruysse, & R. S. Rew (Eds.),
Pharmacokinetics of the macrocyclic lactones: Conventional wisdom and new paradigms (p. 124). Oxon: Macrocyclic Lactones in Antiparasitic
Therapy, Cabi Publishing.
Hong, S. T., Lee, S. H., Lee, S. J., Kho, W. G., Lee, M., Li, S., … Choi, M. H. (2003). Sustained‐release praziquantel tablet: Pharmacokinetics and the treatment of clonorchiasis in bea‐ gle dogs. Parasitology Research, 91(4), 316–320. https://doi. org/10.1007/s00436‐003‐0958‐7
Imperiale, F., Lifschitz, A., Sallovitz, J., Virkel, G., & Lanusse, C. (2004). Comparative depletion of ivermectin and moxidectin milk resi‐ dues in dairy sheep after oral and subcutaneous administration.
Journal of Dairy Research, 71(4), 427–433. https://doi.org/10.1017/
S002202990400038X
Jung, H., Medina, R., Castro, N., Corona, T., & Sotelo, J. (1997). Pharmacokinetic study of praziquantel administered alone and in combination with cimetidine in a single‐day therapeutic regimen.
Antimicrobial Agents and Chemotherapy, 41(6), 1256–1259. https://
doi.org/10.1128/AAC.41.6.1256
Kamimura, H. (2006). Genetic polymorphism of cytochrome P450s in beagles: Possible influence of CYP1A2 deficiency on toxicologi‐ cal evaluations. Archives of Toxicology, 80(11), 732–738. https://doi. org/10.1007/s00204‐006‐0100‐6
Kigen, G., & Edwards, G. (2017). Drug‐transporter mediated interactions between anthelminthic and antiretroviral drugs across the Caco‐2 cell monolayers. BMC Pharmacology and Toxicology, 18(1), 20. https:// doi.org/10.1186/s40360‐017‐0129‐6
Kim, R. B. (2002). Drugs as P‐glycoprotein substrates, inhibitors, and inducers. Drug Metabolism Reviews, 34(1–2), 47–54. https://doi. org/10.1081/DMR‐120001389
Kim, K. H., Kim, C. S., & Kim, J. W. (2001). Depletion of praziquantel in plasma and muscle tissue of cultured rockfish Sebastes schlegeli after
oral and bath treatment. Diseases of Aquatic Organisms, 45(3), 203– 207. https://doi.org/10.3354/dao045203
Kwei, G., Alvaro, R., Chen, Q., Jenkins, H., Hop, C., Keohane, C., … Wang, Z. (1999). Disposition of ivermectin and cyclosporin A in CF‐1 mice deficient in mdr1a P‐glycoprotein. Drug Metabolism and Disposition,
27(5), 581–587.
Lanusse, C., Lifschitz, A., Virkel, G., Alvarez, L., Sanchez, S., Sutra, J., … Alvinerie, M. (1997). Comparative plasma disposition kinet‐ ics of ivermectin, moxidectin and doramectin in cattle. Journal of
Veterinary Pharmacology and Therapeutics, 20(2), 91–99. https://doi.
org/10.1046/j.1365‐2885.1997.00825.x
Li, X. Q., Björkman, A., Andersson, T. B., Gustafsson, L. L., & Masimirembwa, C. M. (2003). Identification of human cytochrome P 450 s that metabolise anti‐parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data. European Journal of
Clinical Pharmacology, 59(5–6), 429–442. https://doi.org/10.1007/
s00228‐003‐0636‐9
Lo, P. K., Fink, D. W., Williams, J. B., & Blodinger, J. (1985). Pharmacokinetic studies of ivermectin: Effects of formulation. Veterinary Research
Communications, 9(1), 251–268.
Maeda, H., Brandon, M., & Sano, A. (2003). Design of controlled‐re‐ lease formulation for ivermectin using silicone. International
Journal of Pharmaceutics, 261(1–2), 9–19. https://doi.org/10.1016/
S0378‐5173(03)00293‐X
Magalhães, V. S., Cid, Y. P., Ferreira, T. P., Medeiros, D. M., de SO Batista, L. C., Correia, T. R., … Scott, F. B. (2016). Evaluation of pharmaco‐ kinetics and efficacy of ivermectin following oral administration in dogs against experimental infection of Ctenocephalides felis felis and Rhipicephalus sanguineus. Veterinary Parasitology, 228, 167–171. https://doi.org/10.1016/j.vetpar.2016.09.004
Mandour, M. E. M., Turabi, H. E., Homeida, M. M., el Sadig, T., Ali, H. M., Bennett, J. L., … Harron, D. W. (1990). Pharmacokinetics of praziquantel in healthy volunteers and patients with schistosomia‐ sis. Transactions of the Royal Society of Tropical Medicine and Hygiene,
84(3), 389–393. https://doi.org/10.1016/0035‐9203(90)90333‐A
Marriner, S. E., McKinnon, I., & Bogan, J. A. (1987). The pharmacokinetics of ivermectin after oral and subcutaneous administration to sheep and horses. Journal of Veterinary Pharmacology and Therapeutics, 10(2), 175–179. https://doi.org/10.1111/j.1365‐2885.1987.tb00097.x Martinez, M. N., & Papich, M. G. (2009). Factors influencing the gastric
residence of dosage forms in dogs. Journal of Pharmaceutical Sciences,
98(3), 844–860. https://doi.org/10.1002/jps.21499
McKellar, Q., & Gokbulut, C. (2012). Pharmacokinetic features of the anti‐ parasitic macrocyclic lactones. Current Pharmaceutical Biotechnology,
13(6), 888–911. https://doi.org/10.2174/138920112800399194
Mealey, K. L., & Meurs, K. M. (2008). Breed distribution of the ABCB1‐1Δ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. Journal of the American Veterinary Medical Association,
233(6), 921–924. https://doi.org/10.2460/javma.233.6.921
Medleau, L., Ristic, Z., & McElveen, D. R. (1996). Daily ivermectin for treat‐ ment of generalized demodicosis in dogs. Veterinary Dermatology, 7(4), 209–212. https://doi.org/10.1111/j.1365‐3164.1996.tb00248.x Mestorino, N., Turic, E., Pesoa, J., Echeverría, J., & Errecalde, J. (2003).
Pharmacokinetics in plasma of ivermectin after its oral (solu‐ tion and tablets) administration to sheep. Journal of Veterinary
Pharmacology and Therapeutics, 26(4), 307–309. https://doi.
org/10.1046/j.1365‐2885.2003.00485.x
Morovján, G., Csokán, P., Makranszki, L., Abdellah‐Nagy, E. A., & Tóth, K. (1998). Determination of fenbendazole, praziquantel and pyran‐ tel pamoate in dog plasma by high‐performance liquid chromatog‐ raphy. Journal of Chromatography, 797(1–2), 237–244. https://doi. org/10.1016/S0021‐9673(97)01195‐3
Na‐Bangchang, K., Kietinun, S., Pawa, K. K., Hanpitakpong, W., Na‐ Bangchang, C., & Lazdins, J. (2006). Assessments of pharmacokinetic drug interactions and tolerability of albendazole, praziquantel and
ivermectin combinations. Transactions of the Royal Society of Tropical
Medicine and Hygiene, 100, 335–345. https://doi.org/10.1016/j.
trstmh.2005.05.017
Oswald, H., Sharkey, M., Pade, D., & Martinez, M. N. (2015). Canine gas‐ trointestinal physiology: Breeds variations that can influence drug absorption. European Journal of Pharmaceutics and Biopharmaceutics,
97, 192–203. https://doi.org/10.1016/j.ejpb.2015.09.009
Paulson, S. K., Vaughn, M. B., Jessen, S. M., Lawal, Y., Gresk, C. J., Yan, B., … Karim, A. (2001). Pharmacokinetics of celecoxib after oral ad‐ ministration in dogs and humans: Effect of food and site of absorp‐ tion. Journal of Pharmacology and Experimental Therapeutics, 297(2), 638–645.
Perez, R., Godoy, C., Palma, C., Cabezas, I., Munoz, L., Rubilar, L., … Alvinerie, M. (2003). Plasma profiles of ivermectin in horses following oral or intramuscular administration. Journal of Veterinary Medicine Series A,
50(6), 297–302. https://doi.org/10.1046/j.1439‐0442.2003.00531.x
Pouliot, J. F., L'Heureux, F., Liu, Z., Prichard, R. K., & Georges, E. (1997). Reversal of P‐glycoprotein‐associated multidrug resistance by iv‐ ermectin. Biochemical Pharmacology, 53(1), 17–25. https://doi. org/10.1016/S0006‐2952(96)00656‐9
Qian, M., Wei, L., Hao, L., & Tang, S. (2017). Pharmacokinetics of new high‐concentration and long‐acting praziquantel oily suspensions after intramuscular administration in cattle. Journal of Veterinary
Pharmacology and Therapeutics, 40(5), 454–458. https://doi.
org/10.1111/jvp.12378
Rastall, R. (2004). Bacteria in the gut: Friends and foes and how to alter the balance. The Journal of Nutrition, 134(8), 2022S–2026S. https:// doi.org/10.1093/jn/134.8.2022S
Seitz, J. A., & Flessland, G. M. (1965). Evaluation of the physical proper‐ ties of compressed tablets I. Tablet hardness and friability. Journal of
Pharmaceutical Sciences, 54(9), 1353–1357. https://doi.org/10.1002/
jps.2600540926
Skalova, L., Szotakova, B., Machala, M., Neca, J., Soucek, P., Havlasova, J., … Lamka, J. (2001). Effect of ivermectin on activities of cytochrome P450 isoenzymes in mouflan (Ovis musimon) and fallow deer (Dama
dama). Chemico‐Biological Interaction, 137, 155–167. https://doi.
org/10.1016/S0009‐2797(01)00227‐7
Sun, Y., & Bu, S. J. (2012). Pharmacokinetics and relative bioavailability of praziquantel in healthy water buffalo after oral and intramuscular administration. Journal of Veterinary Pharmacology and Therapeutics,
35(6), 618–622. https://doi.org/10.1111/j.1365‐2885.2011.01364.x
Szakacs, G., Varadi, A., Ozvegy‐Laczka, C., & Sarkadi, B. (2008). The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME–Tox). Drug Discovery Today, 13(9–10), 379–393. https://doi.org/10.1016/j.drudis.2007.12.010
Tang, S., Chen, L., Guo, Z., Hu, X., He, J., Wang, G., … Xiao, X. (2012). Pharmacokinetics of a new ivermectin/praziquantel oil suspension
after intramuscular administration in pigs. Veterinary Parasitology,
185(2–4), 229–235. https://doi.org/10.1016/j.vetpar.2011.10.021
Tang, S., Chen, L., Qian, M., Hao, L., & Xiao, X. (2016). Pharmacokinetics of a new ivermectin/praziquantel suspension after intramuscular ad‐ ministration in sheep. Veterinary Parasitology, 221, 54–58. https://doi. org/10.1016/j.vetpar.2016.01.024
Taylor, M. (2001). Recent developments in ectoparasiticides. The
Veterinary Journal, 161(3), 253–268. https://doi.org/10.1053/
tvjl.2000.0549
Wacher, V. J., Wu, C. Y., & Benet, L. Z. (1995). Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐ glycoprotein: Implications for drug delivery and activity in cancer chemotherapy. Molecular Carcinogenesis, 13(3), 129–134. https://doi. org/10.1002/(ISSN)1098‐2744
Walther, F. M., Allan, M. J., & Roepke, R. K. (2015). Plasma pharmacoki‐ netic profile of fluralaner (Bravecto™) and ivermectin following con‐
current administration to dogs. Parasites & Vectors, 8(1), 508. https:// doi.org/10.1186/s13071‐015‐1123‐8
Weber, M., Stambouli, F., Martin, L., Dumon, H., Biourge, V., & Nguyen, P. (2001). Gastrointestinal transit of solid radiopaque markers in large and giant breed growing dogs. Journal of Animal
Physiology and Animal Nutrition, 85(7–8), 242–250. https://doi.
org/10.1046/j.1439‐0396.2001.00325.x
Weber, M. P., Stambouli, F., Martin, L. J., Dumon, H. J., Biourge, V. C., & Nguyen, P. G. (2002). Influence of age and body size on gas‐ trointestinal transit time of radiopaque markers in healthy dogs.
American Journal of Veterinary Research, 63(5), 677–682. https://doi.
org/10.2460/ajvr.2002.63.677
Woodward, K. (2005). Veterinary pharmacovigilance. Part 6. Predictability of adverse reactions in animals from laboratory toxi‐ cology studies. Journal of Veterinary Pharmacology and Therapeutics,
28(2), 213–231. https://doi.org/10.1111/j.1365‐2885.2005.00650.x
Zoran, D., Riedesel, D., & Dyer, D. (1993). Pharmacokinetics of propofol in mixed‐breed dogs and greyhounds. American Journal of Veterinary
Research, 54(5), 755–760.
How to cite this article: Ozdemir Z, Faki HE, Uney K, Tras B.
Investigation of pharmacokinetic interaction between ivermectin and praziquantel after oral administration in healthy dogs. J vet Pharmacol Therap. 2019;42:497–504. https://doi. org/10.1111/jvp.12769
