Descriptive statistics were determined using commercially-available software (Microsoft Office Excel 2007). Statistical comparisons were performed using SPSS 16.0 with independent-samples t-test. A p level of 0.05 was considered significant. Data are presented as arithmetic mean ± standard deviation as well as median and range. For graphical presentations of results Microsoft Office Excel 2007 was used.
2.4 Results
2.4.1 Resistance of gabapentin capsules to gastric pH
Both capsules disintegrated under given invivo testing conditions very rapidly. The GBP capsule from a local pharmacy disintegrated within 40 seconds, the GBP ratiopharm capsule disintegrated in 65 seconds (Figure 1). After 6 minutes the capsule was already disintegrated and the contrast medium detectable in the stomach outside of the capsule (Figure 2).
Figure 1 GBP capsule filled with bromphenol in hydrochloride acid medium (pH 3.21) in a beaker heated at approximate body temperature at time of capsule disintegration.
Figure 2 x-ray of a beagle dog 6 minutes after oral administration of a gabapentin capsule filled with bariumsulfate.
The hyperdense spots within the stomach represent bariumsulfate from the disintegrated capsule marked as arrow.
Figure 2 x-ray of a beagle dog 6 minutes after oral administration of a GBPcapsule filled with bariumsulfate. The hyperdense spots within the stomach represent bariumsulfate from the disintegrated capsule marked as arrow.
2.2.2 Influence of general anaesthesia on pharmacokinetics of orally administered gabapentin in beagle dogs
Gabapentin was detectable in serum samples in nine out of ten dogs. In dog b there were no serum concentrations of GBP detectable at any time. One other dog (d) developed diarrhoea during anaesthesia. This dog was treated with metronidazole (Metronidazol 500, B. Braun Melsungen AG, 34209 Melsungen, Germany), amoxicillin (Amoxicillin-sodium, Selectavet, Dr. Otto Fischer GmbH, 83629 Weyarn-Holzollingen, Germany) and balanced electrolyte solution during the study and got further treatment afterwards. In other dogs no adverse effects were observed. Recovery was uneventful in all dogs.
Serum samples in dogs which were immediately anaesthetized after oral application of GBP (group 1) ranged from 1.0 to 12.2 µg ml-1(Figure 3). Because of serum levels with marginal increase above detection limit in group 1 a calculation of absorption kinetics was not possible.
The serum concentration - time curve of each dog had two peak levels, the first one between 2 and 4 hours, the second and higher one between 8 and 16 hours after oral application (Figure 3).
Area under the serum concentration time curve from time 0 to 12 hours (AUC0-12) was 22.29 ± 10.8 h * µg ml-1. Area under the curve > 1 µg ml-1(detection limit) (AUC0-12>1) was 10.29 ± 10.8 h * µg ml-1.
In group 2, where dogs did not undergo anaesthesia, GBP serum levels ranged from 1.00 to 10.29 µg ml-1. Maximum serum concentrations were 4.67 and 9.99 µg ml-1and time to reach the maximum serum concentration was 4.28 and 1.36 h (Figure 4). Elimination half-life was 2.96 and 2.99 h. Total body clearance was 184.03 and 169.62 ml-1kg-1h-1. Area under the serum concentration time curve from time 0 to 12 hours was 48.20 ± 9.41 h * µg ml-1and AUC0-12>1 was 36.20 ± 9.41 h * µg ml-1(Table 5).
In group 3 which received anaesthesia 1 hour after capsule intake GBP serum levels ranged from 1.00 to 6.07 µg ml-1(Figure 4). A peak concentration was reached at 1.62 hours and maximum GBP concentration was 5.73 µg ml-1. Elimination half-life was 2.71 h. Total body clearance was 294.81 ml-1kg-1h-1. Area under the serum concentration time curve from time 0 to 12 hours was 31.98 h * µg ml-1and AUC0-12>1 was 19.98 (Table 5).
Area under the curve 0 - 12 did not differ significantly between groups 1, 2 and 3. Mean AUC 0-12were 22.29 ± 10.80 and 25.97 (group 1 a, c – f, k + l) versus 48.20 ± 9.41 (group 2) and 31.98 41 h * µg ml-1(group 3), (p < 0.05). But median AUC of group 1 and 2 showed a tendency towards differences.
Figure 3 A and BGBP serum concentrations [µg ml-1] from dogs in group 1 which received GBP 10 mg kg-1 orally immediately before 2 hours of anaesthesia. Serum concentrations are measured from baseline to 12 hours A (dogs a-f) and 24 hours B (dogs g-j) respectively. Induction of general anaesthesia is depicted with a blue arrow, end of anaesthesia is depicted by means of a white arrow.
1 10
0 2 4 6 8 10 12 14 16 18 20 22 24
gabapentinserumconcentration[µgml-1]
dog a dog b dog c dog d dog e dog f
time [hours]
1 10
0 2 4 6 8 10 12 14 16 18 20 22 24
gabapentinserumconcentration[µgml-1]
dog h dog i dog j
time [hours]
2 4 6 8
8 6
2 4
Table 2Area under the serum concentration time curve (AUC) for gabapentin of 9 dogs in group 1 which received GBP orally 10 mg kg-1immediately before 2 hours of anaesthesia. AUC calculated from T0to T12h. Detection limit was 1.0 µg ml-1. Dogs a - f were measured over a period of 12 hours, dogs g - j over 24 hours.
range 1.694 - 20.006 14.023 - 32.006
dog
range 1.460 - 34.340 13.460 - 46.340 39.095 – 66.680
Table 3Pharmacokinetic parameters for GBP from dogs out of group 2 and 3. Dogs received GBP orally 10 mg kg-1without anaesthesia (dogs k and l) and GBP orally 10 mg kg-11 hour before 2 hours of anaesthesia (dog m).
Detection limit was 1.0 µg ml-1. AUC: Area under the serum concentration -time curve, calculated from T0to T12h. and T0to T16h, Cmax: maximum serum concentration,Tmax,: time to maximum serum concentration, k01: absorption rate constant, k10: elimination rate constant, Cl: total body clearance, t1/2 abs: absorption half life, t1/2 eli: elimination half life, VD: volume of distribution.
dog k l m
Figure 4GBP serum concentrations [µg ml-1] from dogs in group 2 and 3 which received GBP orally without anaesthesia (dogs k, l) and one hour before 2 hours of anaesthesia (dog m). Serum concentrations are measured from baseline to 16 hours. Arrow marks induction of anaesthesia in dog m. Induction of general anaesthesia is depicted with a blue arrow; end of anaesthesia is depicted by means of a white arrow in dog m.
1 10
0 2 4 6 8 10 12 14 16 18 20 22 24
gabapentinserumconcentration[µgml-1]
time [hours]
dog k dog l dog m
4 6 8
2
1 10
2.5 Discussion
This study shows that an application of GBP immediately before anaesthesia leads to a delayed absorption although overall AUC was not different. Thus we assume effective serum concentrations are not reached during surgery and are questionable in the early postoperative period. If GBP is given at least one hour before anaesthesia absorption is similar to conscious dogs.
In greyhound dogs (KUKANICH & COHEN 2009) the same oral dose of GBP as in the conscious beagle group resulted in similar Tmax(range 0.75 – 2.0 h versus 1.36 – 4.26 h) and Cmaxvalues (range 5.32 – 10.90 µg ml-1versus 4.67 – 9.99 µg ml-1). Area under the curve 0 - 12 hours were 48.20 ± 9.41 h * µg ml-1versus AUC0-inf48.77 h * µg ml-1. Elimination half- life was 2.96 – 2.99 h versus 2.63 – 3.68 h. In other pharmacokinetic studies in dogs higher doses or other routes of application were used (STEVENSON et al. 1997; RHEE et al. 2008). KuKanich and Cohen (2009) also administered 20 mg kg-1to greyhound dogs. This resulted in Tmaxof 1.00 – 2.00 h, a Cmaxof 10.70 – 18.20 µg ml-1and t1/2of 3.07 – 3.91 h. Rhee et al. (2008) administered a single dose of 50 - 60 mg kg-1to beagle dogs. This group reached Tmaxafter 2.00 h and Cmaxwas 32.55 ± 4.49 µg ml-1. Further elimination half-life was 3.1 ± 0.2 h. Stevenson et al. (1997) administered 50 mg of GBP as midjejunal infusion to mongrel dogs. This application resulted in Cmaxof 2.5 ± 0.55 µg ml-1and an AUC0-12of 8.6 ± 0.46 h * µg ml-1.
Since there are no established reference values for effective serum concentrations as analgesic treatment in dogs, it is assumed that they are similar to effective antiepileptic serum concentrations because in human medicine similar doses are used in epilepsy treatment and for analgesia. These plasma levels show a marked interindividual variation and are therefore not used routinely as monitoring parameter. Patsalos and co- workers (2008) advise a reference range of 2 - 20 µg ml-1for adults. Mirza et al. (1999) recommend little lower values of 12 -60 µmol l-1which translates to 2.1 - 10.3 µg ml-1. This implies that effective serum concentrations were not reached during anaesthesia in the majority of dogs.
Area under the curve levels in this study were calculated from time 0 to 12 hours because this was the dose interval. The AUC levels >1 obtained in group 1 were lower than the serum levels in group 2 (10.29 ± 10.8 h * µg ml-1versus 36.20 ± 9.41 h * µg ml-1)showing minor absorption
in group 1. This difference tends to become statistically significant. The most likely explanation for prolonged time until detection of GBP serum levels and lower serum levels obtained in group 1 is the effect of general anaesthesia. Opioids like the employed levomethadone which was given at induction of anaesthesia are known to decrease gastrointestinal motility and gastric emptying thereby indirectly influencing GBP’s absorption. Already Gyang (1964) demonstrated morphin’s capability to inhibit peristaltic reflexes of the stomach (elicited by distension of the bowel). Other authors verified a delay in gastric emptying by opioid agonists (SULLIVAN et al.
1981; ALLESCHER et al. 1988). It is known that the effects of opioids in the stomach differ from that in small intestine because of differences in innervation (BURKS et al. 1982;
SCHEMANN & EHRLEIN 1986; FOX & DANIEL 1987). Interestingly Pfizer referred to a study in which morphine given orally two hours before GBP (in a subanaesthetic dose) caused an increase of GBP’s AUC (ANONYMUS 2009). Other drugs employed in this study like diazepam, isoflurane and propofol also affect gastrointestinal motility to a variable extend.
Steyn et al. (1997) showed that diazepam IV in combination with a meal in conscious cats leads to prolonged gastric emptying. This tendency was also described by Adelhøj (1985) in men. In contrast, Schurizek et al. (1988) and McNeill (1990) found that diazepam increased gastrointestinal motility by enhancing amplitudes of antral contrations. Isoflurane also reduces gastrointestinal transit after brief anaesthesia (TORJMAN et al. 2004) and decreases gastric motility index (HALL et al. 1995). Propofol which was only applied in the induction period of anaesthesia and beyond that has a short duration of action (PLUMB 1999) additionally decreases frequency of gastric motility (SCHNOOR et al. 2005). If propofol is given as sole medication in a subhypnotic dose it does not modify gastric emptying (CHASSARD et al.
2002). A combination of propofol and morphine in comparison to morphine alone did not abolish the delay of gastric emptying induced by morphine but counteracted the effects of morphine on gastric tone: morphine alone decreased gastric tone but the combination of both increased gastric tone (HAMMAS et al. 2001).
In the current study GBP concentration increase showed two peak levels, the first one between 2 and 4 hours, which means directly after end of anaesthesia, the second and higher one between 8 and 16 hours after oral application, implying after end of action of levomethadone.
GBP is mainly absorbed in the small intestine via the L-amino acid transporter system.
Furthermore, although still questioned if passive transports might also play a role (STEWART
et al. 1993; SU et al. 1995; STEVENSON et al. 1997). Stevenson et al. (1997) assume a monosaccharide induced increase in intestinal water absorption since an increase of drug plasma levels occurred after co-administration of sodium co-transported monosaccharides. The prolonged time until detection of GBP in serum could be attributable to altered transporter mechanisms in the small intestinal wall but is not very likely because opioids do not act as substrates for this transporter. Residual of food in the stomach or the kind, volume and time of last food administered could additionally influence GBP’s absorption since the capacity of the transporter for GBP is dependent on presence of other competing substrates: a co-administration of GBP and amino acids leads to a decrease of GBP serum concentration whereas a combination with monosaccharides increases GBP serum concentration (STEVENSON et al.
1997). The gastric pH in the main study - although we did not measure it - might have been lower than that in the in vitro trial. Savvas et al. (2009) investigated the effect of pre-anaesthetic fasting time and kind of food on the gastric pH. They showed if dogs are fasted for 10 h after feeding of dry food, they have a gastric pH of appr. 1.56, this differs from the current study where we provided a pH of 3.21 for the in vitro experiment. In our clinical study the dogs were fasted overnight which means more than 12 h without food. In contrast, it is reported for the related compound pregabalin in humans that the co-administration of food has no clinically relevant effect on the amount absorbed but the rate of absorption is delayed (BEN-MENACHEM 2004; KUGLER 2002).
If the GBP treatment is started before anaesthesia, the time from capsule intake to induction of anaesthesia should be at least 1 hour to receive Tmaxearly during anaesthesia. In our study GBP was administered 1 hour before anaesthesia in just one dog but kinetic was very similar to conscious dogs. If a dog is going to have a surgery (AGHIGHI et al. in prep.), Tmaxshould be achieved favourably before incisional trauma promising prevention of central sensitization also by GBP. Nevertheless serum levels are lower than in conscious dogs although this is just a statistically significant difference if regarding of 10 % because of small group size. Thus further investigations are needed to elucidate the effect of higher initiating dosage pre- surgery to achieve sufficient serum levels in spite of prolonged resorption - although no minimum effective limit is defined for GBP against neuropathic pain in dogs. Another possibility - if emergency surgery is required and anaesthesia time cannot be scheduled - could be the
co-administration of drugs which increase the peristaltic of stomach and intestine but this has to be investigated too.
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3. General discussion
3.1 Materials and methods, study design and study limits
There are limitations to this complex study that should be considered during interpretation of data. The use of different methods to detect the combination of nociceptive and neuropathic
There are limitations to this complex study that should be considered during interpretation of data. The use of different methods to detect the combination of nociceptive and neuropathic