The Pharmacokinetics of Buserelin after Intramuscular Administration in Pigs and Cows

Background: Buserelin is a LHRH agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not clearly understood. This study was designed to develop a sensitive method to determine the concentration of buserelin and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows. Results: A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studies in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC0-t) was 25.02 ± 6.93 h·ng/mL for pigs and 5.63 ±1.86 h·ng/mL for cows. The maximum plasma concentration (Cmax) and time to reach the maximum concentration (tmax) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ±0.27 h for cows, respectively. The apparent volume of distribution (Vz) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t1/2λz), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals. Conclusion: This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.

Disposition Kinetics of Amitraz in Lactating Does

Amitraz, a member of the formamidine pesticide family, commonly used for ectoparasite control, is applied as a dip or low-pressure hand spray to cattle and swine, and the neck collar on dogs. Data on amitraz were generated mainly on laboratory animals, hens, dogs, and baboons. The data on the toxicity and disposition of amitraz in animals and its residues in the milk are inadequate. Therefore, the present study was intended to analyze the disposition kinetics of amitraz and its pattern of elimination in the milk of lactating does after a single dermal application at a concentration of 0.25%. Blood at predetermined time intervals and milk twice daily were collected for eight days post application. The drug concentration was assayed by high-performance liquid chromatography (HPLC). Amitraz was detected in whole blood as early as 0.5 h, which attained a peak concentration at 12 ± 5 h, followed by a steady decline; however, detection persisted until 168 h. Amitraz was present in the blood at its 50% Cmax even after 48 h, and was still detectable after 7 days. The disposition after a single dermal application was best described non-compartmentally. The mean terminal half-life (t1/2), mean residence time (MRT), and area under the curve (AUC0–t) were 111 ± 31 h, 168 ± 39 h, and 539 ± 211 µg/mL/h, respectively. The apparent volume of distribution (Vdarea) was 92 ± 36 mL/g with an observed clearance (Cl) of 0.57 ± 0.33 mL/kg/h. Thus, the drug was well absorbed, widely distributed and slowly eliminated from the animal body. Amitraz achieved milk concentration approximating 0.2 per cent of the total dose after a single exposure and the steady-state elimination of amitraz in milk above the recommended maximum residue limit (MRL) of 0.01 mg/kg can act as a source of public health concern when applied on lactating animals.

Pharmacokinetics of Marbofloxacin Following Oral Administration in Piperine, Quercetin Alone and Both in Combination Pretreated Broiler Chickens

Background: Various antibacterial drugs are substrates for drug metabolizing enzymes. They suffer from reduced bioavailability after oral administration in chickens. Herbal bio-enhancers increased the absorption of co-administered drugs. Hence, present study was planned to explore the bio-enhancing effect of piperine and quercetin pretreatment on pharmacokinetics of marbofloxacin after oral administration in broiler chickens.Methods: The pharmacokinetics of marbofloxacin was investigated following single dose (5 mg/kg) oral administration in piperine, quercetin alone and both in combination pretreated (10 mg/kg each, oral, 3 days) broiler chickens. The concentrations of marbofloxacin in plasma samples were analyzed by high performance liquid chromatography.Result: Following single oral administration of marbofloxacin, elimination half-lives (t1/2β) were 6.23 ± 1.01, 5.69 ± 0.39 and 7.71 ± 0.59 h in piperine, quercetin and both in combination pretreated chickens, respectively. The elimination half-life (t1/2β), apparent volume of distribution (Vd(area)/F) and mean residence time (MRT) were significantly (p less than 0.05) higher in combination pretreated chickens as compared to piperine and quercetin alone groups. Piperine and quercetin combined pretreatment has improved the pharmacokinetics profile of marbofloxacin after oral administration in broiler chickens. Findings of the study are expedient for the development of protocol for use of bio-enhancers with antibiotics in broiler chickens.

An HPLC–MS/MS method for quantitation of trelagliptin and application in a comparative pharmacokinetic study

Aim: A sensitive HPLC–MS/MS approach was established to quantify trelagliptin and explore the pharmacokinetic characteristics in rats for up to 7 days. Meanwhile, the pharmacokinetic differences of trelagliptin were investigated for the first time. Results/methodology: The ion pairs of m/z 358.2→341.2 for trelagliptin and m/z 340.3→116.1 for alogliptin (internal standard) were detected in positive mode. Trelagliptin displayed a good linearity in the range of 4–4000 ng/ml (r2 = 0.9997) with a mean recovery rate of 86.9–94.1%. Discussion/conclusion: Compared with normal groups, the T1/2, apparent volume of distribution, area under the curve and bioavailability in model rats were significantly increased while the apparent plasma clearance decreased. The approach is proved to be straightforward and appropriate for quantitation of trelagliptin and application in pharmacokinetics studies.

Effects of Xuesaitong on the Pharmacokinetics of Losartan: An In Vivo UPLC-MS/MS Study

The aim of this study was to examine whether Xuesaitong, a multiherbal formulation for coronary heart disease, alters the pharmacokinetics of losartan. Adult male Sprague Dawley rats randomly received losartan (10 mg/kg) or losartan plus Xuesaitong (10 mg/kg) through an oral gavage (n = 6). Multiple blood samples were obtained for up to 36 h to determine the concentrations of losartan and its active metabolite, EXP3174, through ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetics were estimated using a noncompartmental model. The half-life (t1/2) of losartan was decreased by Xuesaitong (4.26 ± 1.51 vs. 6.35 ± 2.10 h; P<0.05). The apparent volume of distribution (Vd) of losartan was also decreased by the combination of losartan and Xuesaitong (4.41 ± 1.61 vs. 7.20 ± 2.41 mL; P<0.05). The time to maximum concentration (Tmax) of losartan was increased by Xuesaitong (1.06 ± 1.04 vs. 0.13 ± 0.05 h; P<0.05). Xuesaitong also decreased the t1/2 of EXP3174 (8.22 ± 1.41 vs. 6.29 ± 1.38 h; P<0.05). These results suggest that there is a complex interaction between losartan and Xuesaitong. In addition to enhanced elimination of losartan and EXP3174, Xuesaitong may also decrease the absorption rate and Vd of losartan.

P019 Treating conjoined twins

SituationD and M are conjoined twins born without an antenatal diagnosis and assessed as not suitable for separation. At the time of admission they were 21 months old with a combined weight of 17.1 Kg. D presented unwell with a raised heart rate and respiratory rate. A working diagnosis of sepsis (possibly urinary tract infection) was made. Advice was sought from pharmacy on the doses of ceftriaxone and paracetamol. Peripheral intravenous (IV) access was only available in twin M.BackgroundThe twins are joined side by side from the upper chest to the pelvis. They have separate heads, three arms and 2 legs. They have 2 hearts with a fused aorta, a shared liver, 2 gallbladders, 2 stomachs, 3 kidneys and a single bladder. D has a complex congenital heart condition and a poor prognosis. On admission, D was receiving propranolol, but M was not. The dose was based on the combined weight of the twins divided by 2. Conjoined twins are a rare phenomenon, occurring 1 in 50,000 to 100,000 births.1 Around 60% of these are stillborn or die shortly after birth. There are many different types of join with differences in shared organs and limbs. Consequently each twin pair is almost unique and consideration must be given as to how medication is dosed according to pharmacokinetic principles.OutcomeOpinion of the multidisciplinary team was that the twins have relatively separate circulations, although some cross-circulation would be expected. On admission, saturations in the right arm (twin D) were 75%. On the left side (twin M) this was 95%. Ceftriaxone is a highly protein bound, hydrophilic antibiotic,2 The degree of cross circulation (how much blood volume is shared between the twins) would affect the volume of distribution and hypoalbuminaemia was likely to increase the apparent volume of distribution. Based on this, ceftriaxone dosing was advised on the combined weight of the twins and given at 50 mg/Kg to M only. Ceftriaxone is excreted mainly unchanged in the urine and bile with little renal clearance or hepatic metabolism so this was not a concern. After 2 days, Ds CRP had reduced and the twins were switched to oral amoxicillin. Dosing was based on the combined weight of the twins and each was given half the dose. As each twin has a separate stomach, it was assumed relatively individual enteral absorption occurs. Ds CRP continued to drop and the twins were discharged home on day 4 with a further 3 days of oral amoxicillin. Paracetamol dosing was advised at 15 mg/kg based on the combined weight and half given to each twin. As required use was agreed, as there was uncertainty over the amount of hepatic metabolism that would occur by the twins shared liver.Lessons learntConjoined twins are a complex yet interesting challenge in terms of medication dosage and administration. There is a lack of evidence and dosing has been based on pharmacokinetic principles and adjusted according to clinical response.ReferencesOwolobi AT, Oseni SB, Sowande OA, et al. Dicephalus dibrachius dipus conjoined twins in a triplet pregnancy. Tropical Journal of Obstetrics and Gynaecology 2005;22:87–88.Electronic Medicines Compendium: Rocephin 1g powder for solution for injection or infusion - Summary of Product Characteristics. http://www.emc.org.uk/(Accessed 12 Jun 2018)

Tacrolimus Pharmacokinetics in Living-Donor and Deceased-Donor Liver Transplant in Saudi Patients

Introduction: Tacrolimus is a macrolide immunosuppressant. It has a narrow therapeutic index and serious side effects which necessitate monitoring of tacrolimus blood concentration. The trough concentration of the drug may also differ based on the type of liver transplant. This study was conducted to investigate differences in pharmacokinetics between transplant types and to determine tacrolimus population pharmacokinetic in liver transplant recipients in Saudi Arabia. Method: Patients on tacrolimus, as the main immunosuppressant, who underwent liver transplant throughout2012-2014 were retrospectively studied. Demographic characteristic, tacrolimus blood trough concentrations, liver, renal, biochemistry, and hematology lab results were all collected. The pharmacokinetic parameters were estimated assuming one compartment model. Results: Tacrolimus pharmacokinetic parameters were found to be as following; elimination rate constant () 0.094 ± 0.0123, apparent volume of distribution () 112.48±63.033 L/hr, elimination half-life () 7.46± 1.01 hr and apparent total body clearance () 10.27± 5.69 L/hr (mean ± SD). Statistically significant difference was found between living-donor and deceased-donor liver transplant with respect to apparent clearance and apparent volume of distribution. Living-donor liver transplant recipients have apparent volume of distribution of 97.39±47.00 L (mean ± SD) and an apparent clearance of 8.89±4.24L/hr (mean± SD). On the other hand, deceased-donor liver transplant has an apparent clearance of 12.97±7.09L/hr (mean ± SD) and an apparent volume of distribution of 142.17± 78.65 L (mean ± SD). Conclusions: Tacrolimus pharmacokinetics parameters were accurately determined in liver transplant recipients in Saudi Arabia. The results of the present study can be clinically used in the therapeutic drug monitoring of tacrolimus in the individualization of drug dosage and taking the appropriate clinical decisions to prevent allograft rejection.

An LC-MS/MS Method for Synchronous Determination of Paclitaxel and Curcumin: Development, Validation, and Application to a Pharmacokinetic Study

Background: A chromatography tandem mass spectrometry method was first established and validated for the synchronous determination of curcumin(CUR) and paclitaxel (PTX) in this study. </P><P> Objective: An LC-MS/MS Method for Determination of Paclitaxel and Curcumin. Methods: The analytes were extracted with methanol, and docetaxel was used as the internal standard (IS). The analytes and the IS were separated on a C18 (4.6 mm × 50 mm, 3.5 µm) column with a mobile phase of 0.1% formic acid solution and methanol (80:20, v/v). The flow velocity of the mobile phase was 0.5 mL/min. And then, the method was applied to study the pharmacokinetic behavior of CUR and PTX in rats. Results: The calibration curves were linear within the concentration ranges of 2–1000 ng/mL for PTX and 5–500 ng/mL for CUR, the mean extraction recoveries and matrix effects of PTX, CUR, and the IS were within an acceptable range. The apparent volume of distribution of PTX was different between the group of administration of PTX and the group of co-administration with CUR and PTX. Conclusion: A sensitive and simple liquid chromatography-tandem mass spectrometry method was established and validated for the synchronous determination of PTX and CUR in rat plasma, CUR increased the apparent volume of distribution of PTX when CUR and PTX were co-administered.

Influence of Resveratrol on the Pharmacokinetics and Pharmacodynamics of Naproxen: Involvement of CYP1A2 Inhibition

The purpose of the present study was to assess the effect of resveratrol (RSV) on the pharmacokinetics of naproxen (NAP) in rats. A single dose of RSV 30mg/kg was administered once during treatment phase. A single dose of NAP 25mg/kg was administered after RSV treatment. The blood samples were collected after NAP dosing at predetermined time intervals and analyzed by HPLC. In comparison with the control, RSV pretreatment significantly enhanced maximum plasma concentration (Cmax), area under the curve (AUC), and half life (t1/2) and significantly decreased apparent oral clearance (CL/F) and apparent volume of distribution (Vd/F), while there was no significant change observed in time to reach maximum concentration (tmax) of NAP. The results suggest that the altered pharmacokinetics of NAP might be attributed to RSV-mediated inhibition of CYP1A2 enzyme. Therefore, combination therapy of NAP along with RSV may represent a novel approach to reduce dosage and results in reduced gastrointestinal side effects of NAP.