K.C. Carlsson(1), M. Bergjord(1), E.R. Moberg(2) and N.O. Hoem(1)
(1) Department of Pharmacology, School of Pharmacy, University of Oslo, Norway, (2) Institute of Pharmacology, Faculty of Medicine, University of Oslo, Norway.
Introduction: Gabapentin has a demonstrated analgesic effect in patients with chronic neuropathic pain states 1 and is well established in the treatment of seizures. Gabapentin does not bind to plasma proteins and is excreted unchanged in the kidneys. Gabapentin displays dose dependent, saturable absorption. This is believed to include an active transport process mechanism by an L-amino acid transporter 2. This absorption pattern is believed to explain lack of effect in many patients due to sub-optimal dosing, but also low toxicity since high doses will be less absorbed 3.
Methods: Patients with chronic, neuropathic pain receiving gabapentin as their main pain treatment were included in the study. The subjects were monitored during one dose interval (6-8 h) when in steady state. The bladder was emptied before the gabapentin dose was taken. Total urine volumes were measured and gabapentin concentrations measured by LC/MS-MS 4. An estimate of excreted gabapentin pr 24 h were calculated based on the length of urine collection, urine volume and concentration of drug in the urine. An estimate for bioavailability estimated from urine collection (FU) was calculated by using the following formula:
FU = (amount excreted in urine in mg/24 h)/DD
where DD is daily dose of gabapentin. These estimates were compared to estimates found by using a model for gabapentin absorption developed by Gidal et al. 5 These authors report a Michaelis-Menten relationship between F and DD where the bioavailability estimated by the model (FM) was found to be:
 FM = Dmax / (D50 + DD), Dmax = 2720 mg/day and D50 = 4080 mg/day.
Results: A good agreement was found between the two estimates of F. The model was able to predict an estimate of F close to the measured value in five out of seven patients. Average bioavailability for the seven patients was almost the same for model and urine collection, 42.5% and 43.7% respectively.
Conclusions: These results demonstrate that the absorption model can be included in pharmacokinetic models to be used in the monitoring of gabapentin.
References:
1. Rowbotham M, Harden N, Stacey B, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. Jama. 1998;280:1837-1842.
2. Stewart BH, Kugler AR, Thompson PR, et al. A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma. Pharmaceutical Research. 1993;10:276-281.
3. McLean MJ, Gidal BE. Gabapentin dosing in the treatment of epilepsy. Clinical Therapeutics. 2003;25:1382-1406.
4. Carlsson KC, Reubsaet JLE. Sample preparation and determination of gabapentin in venous and capillary blood using liquid chromatography-tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis. 2004;34:415-423.
5. Gidal BE, DeCerce J, Bockbrader HN, et al. Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy. Epilepsy Research. 1998;31:91-99.
Reference: PAGE 14 (2005) Abstr 777 [www.page-meeting.org/?abstract=777]
Poster: poster