Pharmacokinetics of low-dose and high-dose buprenorphine in cats after rectal administration of different formulations

Abstract

Objectives

A prospective experimental study was performed in nine young healthy cats to investigate a pharmacokinetic profile and the clinical relevance of rectally administered buprenorphine. Rectal pH value was measured in all nine cats.

Methods

Blood was collected 15, 30, 60, 90, 120, 240 and 480 mins and 24 h after the rectal administration of a suppository and a gel at doses between 0.02 mg/kg and 0.1 mg/kg buprenorphine to determine the plasma concentration of buprenorphine. Rectal pH was measured with pH paper.

Results

Upon pharmacokinetic non-compartment analysis of high-dose buprenorphine (0.1 mg/kg), average maximal plasma concentration was found to be 1.13 ng/ml, time to maximal plasma concentration was 45 mins and area under the plasma concentration–time curve was 94.19 ng*min/ml, representing low but potential bioavailability. Mean residual time was 152.2 mins and the half-life was 92.6 mins. A wide range of plasma concentrations within the cohort was measured and two of the cats had to be excluded from statistical analysis owing to incomplete uptake. Vital parameters of all cats were considered to be normal but three of the cats showed mydriasis up to 8 h after application. After the administration of a low-dose suppository or a rectal gel (0.02 mg/kg) within pilot studies, no buprenorphine was detected in cat plasma. Rectal pH in all cats was between 7.7 and 8.

Conclusions and relevance

The rectal application of buprenorphine at a dose of 0.1 mg/kg revealed a potential but weak uptake in cats. Regarding effective concentrations in previous pharmacokinetic investigations, rectal administration is currently not recommended for good provision of opioid analgesia in cats. Pharmacological investigations of formulation and galenics in order to improve the rectal bioavailability of buprenorphine remain to be clarified before further dose-finding and pharmacokinetic/pharmacodynamic studies are performed.

Keywords

Buprenorphine rectal administration plasma concentration bioavailability

Introduction

As a potent opioid in human and veterinary medicine, buprenorphine is an established analgesic for dogs and cats.^1–7 In Germany, buprenorphine is licensed for intravenous (IV) or intramuscular (IM) application in dogs and cats.

As a lipophilic opioid with morphine-like effects, buprenorphine is attributed a partial affinity to the mu opioid receptor, responsible for analgesia, sedation, euphoria, miosis, bradycardia and respiratory depression, as well as an antagonistic affinity to the kappa receptor, which is accountable for analgesia, sedation, bradycardia and hypertonia.^8,9

Apart from IV administration, several studies proved an excellent uptake of buprenorphine in cats at doses between 0.01 mg/kg and 0.12 mg/kg given IM.^10,11 Moreover, good uptake after oral transmucosal administration at doses between 0.01 and 0.12 mg/kg has been described in cats.^12–14 A weaker uptake has been described for the subcutaneous (SC) route at doses between 0.01 and 1.2 mg/kg,^4,15–18 the epidural route at a dose of 0.02 mg/kg^19,20 and following transdermal administration at a dose of 35 µg/h.²¹

In rats, the bioavailability of buprenorphine has been experimentally determined after IV, SC, transdermal and epidural application; furthermore, rectal bioavailability was 54%.²²

In human medicine, rectal suppositories can be seen as a useful route of administration, especially in the case of vomiting patients or those with dysphagia.²³ In addition, a decisive advantage lies within the avoidance of the first-pass effect, meaning there is no direct metabolism of the active substance in the liver via the portal vein.²⁴ Apart from established sublingual tablets of buprenorphine, a good uptake via suppositories has been recorded in humans.^25,26

Unfortunately, there is still insufficient knowledge in the veterinary literature on the bioavailability of opioids after rectal administration. Available reports often describe different findings, influenced by distinctions within animal species, anatomical and physiological differences, as well as physical conditions.⁴ To our knowledge, the bioavailability of buprenorphine after rectal application in cats has not been determined yet. Hence, the aim of the study was to test for a new route of recommended administration with a high bioavailability in cats. Even though the oral transmucosal administration also spares the patient an injection, it often requires sufficient fixation of the patient’s head. Furthermore, the patient often swallows a part of orally administered medication, which consequently leads to a reduced uptake. The rectal route of administration is supposed to be less stressful than the oral transmucosal administration, less painful than an injection and thus connected to an enormous reduction of stress for cats without a venous catheter, owners and veterinary surgeons.

As a high uptake of the opioid is an essential prerequisite to ensure efficient analgesia, the following study aimed to investiage the plasma concentration of buprenorphine in order to provide a pharmacokinetic profile, taking different doses and formulations into consideration.

Materials and methods

Animals

All procedures and protocols were conducted in accordance with the guidelines of the Protection of Animal Act. The study was also approved by the representative of the Chair of Animal Welfare of the Faculty of Veterinary Medicine of the Ludwig Maximilians University, as well as the Government of Upper Bavaria (reference number 55.2-1-54-2532-174-2016). Six male and three female adult, dewormed and routinely vaccinated experimental cats were included in the study. Mean age was 2.3 years (range 2–4 years) and mean body weight was 4.3 kg (range 3.8–5.8 kg). Enrolled animals were considered to be healthy, based on history, clinical examination, complete blood cell count and selected serum parameters (creatinine, urea and alanine aminotransferase). During the study, all animals were clinically examined, focusing on general condition, mucous membrane colour, capillary refill time, respiratory and heart rate and possible side effects.

Drug formulations

The suppository

Each suppository consisted of Buprenaddict Sublingal Tablets (Hexal), gelatin, purified water and glycerol 85%. Each suppository contained 0.1 mg (0.02 mg/kg); diameter was 0.5–0.7 cm and length was 3.2 cm.

The rectal gels

The rectal gels consisted of buprenorphine hydrochloride (Temgesic vials 0.3 mg; Individor) and hydroxyethyl cellulose. Each low-dose tube contained 0.1 mg buprenorphine (0.02 mg/kg) dissolved in a volume of 0.17 ml. Each high-dose tube had a volume of 0.35 ml and contained 0.5 mg buprenorphine, meaning 0.1 mg/kg buprenorphine, taking mean animal weight into account (Figure 1).

Figure 1

Rectal tube contained buprenorphine hydrochloride and hydroxyethyl cellulose

Drug administration

Within a pilot study low-dose suppositories (0.02 mg/kg) were administered to four cats. Four other cats received the same dose of buprenorphine (0.02 mg/kg) formulated in rectal gel as described above.

For the main study a dose of 0.1 mg/kg buprenorphine dissolved in rectal gel was administered to nine cats. A minimum washout period of 14 days between the pilot studies and of 56 days between pilot and main study was granted between treatments.

Blood sampling

The protocol for blood sampling was kept constant for all phases of the study (pilot studies and main study): fur was clipped over the right and left cephalic veins, cleaned with water and disinfected. Before drug administration blood for baseline parameters was taken using a sterile 21 G cannula. Further blood samples were collected in heparin tubes from one of the cephalic veins 15, 30, 60, 90, 120, 240 and 480 mins and 24 h after rectal application. Sample volume was 1 ml for each time point.

Measurement of buprenorphine in plasma

All samples were centrifuged (Centrifuge Heraeus Sepatech) for 15 mins at 2937 g and plasma was stored in tubes at −20°C. For the measurements, the samples were stored and sent on dry ice to TOXILAB (Laboratory for Toxicology and Drug analysis, Ludwigsburg, Germany), for liquid chromatography mass spectrometric analysis, as this method is considered to be an appropriate analysis for a pharmacokinetic profile of buprenorphine.²⁷

Calibration standard and quality control had been established: after the addition of the deuterated standards buprenorphine-d4 and norbuprenorphine-D3 to calibration standard, quality control sample and plasma samples of the cats, protein precipitation was performed employing a solution of 70% methanol and 0.05 M zinc sulphate.

The examination was carried out with high-pressure liquid chromatography (pump: Shimadzu LC-20ADXR; autosampler: Shimadzu SIL-20ACXR; column: Agilent 4.6 × 5.0 Zorbax Eclipse × DB 1.8 µ C18; solvent mixture A: aqueous, 10 mmol/l ammonium acetate, pH 9.4; solvent mixture B: methanolic, 0.1% formic acid), as well as a tandem mass spectrometry (gadget: AB Sciex API 6500) following data analysis.

Biometric data analysis

A pharmacokinetic profile based on measured plasma concentrations of buprenorphine was established with the help of Softwaretool ‘PKSolver 2.0’, appropriate for pharmacokinetic non- compartment analysis.²⁸

Measurement of the rectal pH

Rectal pH was measured in all nine cats with the help of pH paper that was placed rectally (1.5 cm depth) for 10 mins. Rectal pH values were determined based on the appropriate colour scale.

Results

Pharmacokinetic profile

As a result of biometric data analysis of 0.1 mg/kg buprenorphine (Table 1), average maximal plasma concentration (C_max) was 1.13 ng/ml (0.62–1.82 ng/ml) and average time to maximal plasma concentration (T_max) was 45 mins (range 15–90 mins). The area under the plasma concentration–time curve (AUC₂₄), representing rectal bioavailability, was 94.19 ng*min/ml; the mean residual time (MRT) was 152.8 mins and the half-life (t_½) was 92.58 mins. Data analysis demonstrated a great spread of plasma concentrations within the cohort. All plasma concentrations are presented in Figure 2.

Table 1

Mean and median pharmacokinetic variables after 0.1 mg/kg of rectal buprenorphine

Variable	Mean	Median
C_max (ng/ml)	1.13	1.14
T_max (mins)	45	52.5
AUC_²⁴ (ng*min/ml)	94.19	103.37
MRT (mins)	152.8	130.99
Half-life (mins)	92.58	76.05

C_max = maximum observed buprenorphine concentration value; T_max = time point at which C_max occurs; AUC = area under the plasma concentration–time curve; MRT = mean residence time of buprenorphine in the body

Figure 2

Plasma concentration–time curve of all cats in the present investigation

Pilot studies showed that no buprenorphine could be detected in cat plasma at a dose of 0.02 mg/kg, independently of suppository or rectal gel formulation.

Side effects

All vital parameters of the entire cohort were considered to be normal before, during and after the performance of the pilot studies, as well as the main study. Three of the animals showed mydriasis between 30 mins and 8 h after application of the high-dose rectal gel.

Handling

The application of the suppositories and the rectal tubes was performed easily and fast in seven animals, even though all animals had to be held by a second person in order to be fixated. In two cats an unknown amount of rectal gel was lost during the administration due to movement of the animal. They were excluded from statistical analysis as no buprenorphine was detected in their blood samples. None of the other cats showed signs of discomfort such as vocalisation or attempts to escape.

Rectal pH

Rectal pH was 8 in six cats and 7.7 in three cats.

Discussion

With an AUC₂₄ of 94.19 ng*min/ml after rectal administration of 0.1 mg/kg buprenorphine gel, the current investigation demonstrated a weak rectal bioavailability of buprenorphine in cats. This value seems especially low when compared with the results of other studies: Robertson et al registered an AUC₂₄ of 2429.9 ng*min/ml after the oral transmucosal administration of 0.02 mg/kg buprenorphine in cats.³ An MRT of 152.8 mins and a t_½ of 92.58 mins in the present study reflects a fast offset of buprenorphine in plasma. However, following IV and oral transmucosal administration, Robertson et al measured a t_½ of 368.3 mins and 242.7 mins.³ C_max reached 1.8 ng/ml in the current investigation. In comparison, Robertson et al recorded a median C_max of 7.5 ng/ml (range 5.4–12 ng/ml) following oral transmucosal administration of 0.01 mg/kg.

Individual physiological conditions such as the pH value might have an influence on the uptake of buprenorphine, as is described in studies of oral transmucosal administration.^12,13 As a weak base with a pKa of 8.42,⁸ buprenorphine is attributed to have a good uptake in the mouth of cats, where the pH value lies between 8 and 9.¹⁴ The present investigation revealed a rectal pH between 7.7 and 8. Even though a lower pH would explain a lower uptake of buprenorphine, it is still questionable whether this small difference in rectal pH of oral compared with rectal mucosa explains the impaired rectal resorption of buprenorphine.

In order to determine the intrinsic activity of buprenorphine in rectal and peripheral tissue, an ex vivo investigation might be necessary. Watanabe et al compared several rectal formulations of buprenorphine prepared with water-soluble dietary fibres, xanthan gum and locust bean gum in rabbits.²⁹ The authors described that absorption of buprenorphine was different depending on the formulation used. This is why we chose to test different drug vehicles – namely a suppository and a rectal gel – during our pilot studies. Investigations of formulation and galenics to improve the rectal uptake of buprenorphine, in cats remain to be clarified before further dose-finding and pharmacokinetic/pharmacodynamic studies are performed.

In addition, taking the anatomical aspect into consideration, the individual location of venous discharge via the cranial, medial and caudal rectal veins and its anastomoses might represent an important factor for good uptake. Rectal administration aims at avoiding direct metabolism of the active substance in the liver via the portal vein. The application of a rectal gel including a contrast medium could verify the venous discharge via the medial and caudal rectal veins with the help of appropriate imaging modalities.

As it was the primary aim of this study to evaluate whether, and to what extent, buprenorphine is taken up following rectal administration in feline patients, no pharmacokinetic/pharmakodynamic modelling was performed in the current study. However, comparison of these values with the results of other studies reveals that measured plasma concentrations might not suffice for an analgesic effect: as mentioned previously, C_max in the present study did not exceed 1.8 ng/ml.

Robertson et al investigated the pharmacokinetics and pharmacodynamics after IV and oral transmucosal application of buprenorphine in six cats.³ They estimated the analgesic effect by measuring thermal threshold, which was found to be a reliable way to test the analgesic effect of opioids.³⁰ An increased thermal threshold was measured at plasma concentrations between 1.41 and 4.15 ng/ml after IV application and between 1.26 and 8.26 ng/ml after oral administration.

Hedges et al described the maximal analgesic effect on the basis of thermal threshold at plasma concentrations between 3.9 and 8.2 ng/ml after oral administration in six cats.¹³

However, plasma concentrations and the analgesic effect of buprenorphine are not directly correlated. Trying to match a distinct plasma concentration of buprenorphine to a measurable analgesic effect seems difficult, as a delay between C_max and maximal analgesic effect has been described. The aetiology of the so-called ‘hysteresis effect’ has not yet been fully clarified. The authors discuss several theories in respect to the intrinsic activity of buprenorphine, slow blood–brain equilibration and influence on receptor affinity being responsible for the delayed effect.³

Concentrating on side effects, the phenomenon of euphoria and dysphoria and their distinction from decreased or increased comfort behaviour should be discussed. Robertson et al described euphoria, including rubbing and rolling, and only rare occasions of vomiting, nausea, dysphoria and hyperthermia.^1,3 Steagall et al also documented mydriasis and recorded euphoric rubbing, as well as kneading with the forepaws.³¹ With regard to future dose-finding studies in cats, the wide spread of plasma concentrations within the current cohort is not to be underestimated in order to prevent an overdose in those cats in which the highest uptake of buprenorphine was recorded.

In the current study the cats were kept under constant surveillance of familiarised caretakers and samplers. Except for mydriasis, no side effects were observed.

Temperament, method of restraint and tolerance of rectal manipulation determine the practicability of rectal administration in cats. This route of administration subjectively seems to be less stressful than an IM or SC injection and comparable to the measurement of the rectal temperature. The application of a suppository may be preferential towards a rectal gel, under the premise of an adequate galenic formulation.

Conclusions

The study represents a potential but weak uptake of buprenorphine in cat plasma after rectal application. At a dose of 0.1 mg/kg this route of administration provides low plasma concentrations of buprenorphine. Nonetheless, regarding effective concentrations in previous pharmacokinetic investigations, rectal administration is currently not recommended for good provision of opioid analgesia. Physiological and pharmacological factors, which might explain a weak bioavailability of rectally administered buprenorphine in cats, remain to be clarified in further studies before future dose-finding and pharmacokinetic/pharmacodynamic studies are performed.

Footnotes

Accepted: 08 October 2018

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Maike Schroers

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