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Misc Getting the most of Gabapentin

Connor the Alien

Greenlighter
Joined
Jul 13, 2012
Messages
35
Hi all, would just like to share the best method of taking gabapentin and getting the most out of it, I stumbled on some papers comparing different foods and their absorption effect on gabapentin. If you can't be bothered to read the paper (its not long) I'll inform you know that a high fat meal increases bioavailibility, as does an "isotonic solution of 50 mM D-glucose, (I believe is something like a a saline solotion of glucose), but I/d speculate a carbonated drink would be a suitable substance. Also rectal adminstration also showed no benefit in the efficay of gabapentin (see paper at the bottom)

So I think the trick is to eat a fatty meal with your gabapentin, and then wash it down with a carbonated drink.

After re-reading the paper it seems that protein also plays a role in the absorption level.

Here is the paper I read:


Gabapentin Absorption:
Effect of Mixing with Foods of Varying Macronutrient Composition
Barry E Gidal, Melissa M Maly, Jonathon W Kowalski, Paul A Rutecki, Michael E Pitterle, and Donna E Cook


OBJECTIVE: To compare the oral absorption profile of gabapentin
following administration of the contents of opened capsules that
were mixed with food vehicles of varied macronutrient (protein)
composition.
DESIGN: An unblinded, randomized, single-dose, four-way crossover
pharmacokinetic study in nine healthy adult men and women
volunteers.
METHODS: Following an overnight fast, a single 600-mg dose of
gabapentin (2 × 300-mg Neurontin capsules) was given either as an
intact capsule swallowed with 120 mL of tap water (control, phase
I), or after capsule contents were opened and mixed with; 4 oz. of
applesauce (phase II), 120 mL of orange juice (phase III), or 4 oz. of
fat-free chocolate pudding (phase IV). Subjects fasted for 4 hours
following drug ingestion. Serial venous blood samples were
obtained over 24 hours to determine gabapentin serum
concentrations. Pharmacokinetic variables including AUC,
maximum serum concentration (Cmax), and time to maximum serum
concentration (tmax) were calculated by using standard
noncompartmental methods. Subjects served as their own controls,
and were randomly crossed over following a minimum 7-day
washout period. Statistical analysis was performed by using
ANOVA and Student’s t-test where appropriate.
RESULTS: No statistically significant differences in any kinetic
variable were found between any study arm. A trend was noted for a
modest increase in both Cmax and AUC in phase IV (chocolate
pudding) compared with control (+18.6% and +13.2%,
respectively). In a comparison of protein (phase IV) versus
nonprotein phases (phases I–III), gabapentin AUC was 26% greater
(47.28 ± 14.65 vs. 37.43 ± 9.78 μg/mL• h; p = 0.03), and Cmax was
32% higher (4.72 ± 1.04 vs. 3.56 ± 0.92 μg/mL; p = 0.003).
CONCLUSIONS: Opening and mixing the contents of gabapentin
capsules does not significantly impair drug absorption. This may be
a viable administration option for patients who are unable to
swallow intact capsules. Dietary macronutrient composition (i.e.,
protein) may favorably influence gabapentin oral absorption.
Ann Pharmacother 1998;32:405-9.
GABAPENTIN is an antiepileptic drug that is indicated for the
treatment of partial seizures both with and without secondary
tonic–clonic seizures in patients older than 12 years
of age. It is unique in that it is not metabolized, and absorbed
drug is eliminated primarily by glomerular filtration.
1 Gabapentin has been shown to be a substrate for the
L-amino acid transport system (system L) in mammalian
cells, and is found in both the small intestine and at the
blood–brain barrier. Gabapentin appears to be poorly absorbed
in the colon.2 Gabapentin also displays dose-dependent
absorption, most likely due to saturation of system L.1
In general, food does not appear to impair the absorption of
gabapentin; in fact, it has been demonstrated that meals
containing large amounts of protein significantly increases
the maximal peak serum concentration of gabapentin.3
Given the demonstrated efficacy of this compound, as
well as its relatively mild adverse effect profile and lack of
drug interactions, it is reasonable to expect that this compound
may be used in a variety of patient populations, including
the elderly and children. It is reasonable to speculate
that in these particular populations, alternative oral administration
techniques, such as opening capsules and mixing
The Annals of Pharmacotherapy 1998 April, Volume 32 405
Gabapentin Absorption:
Effect of Mixing with Foods of Varying Macronutrient Composition
Barry E Gidal, Melissa M Maly, Jonathon W Kowalski, Paul A Rutecki, Michael E Pitterle, and Donna E Cook
Neurology
Barry E Gidal PharmD, Associate Professor, School of Pharmacy and Department of
Neurology, University of Wisconsin, Madison, WI
Melissa M Maly RN, Epilepsy Case Manager, Comprehensive Epilepsy Program,
University of Wisconsin
Jonathon W Kowalski PharmD, Research Fellow, College of Pharmacy, University
of Arizona, Tucson, AZ
Paul A Rutecki MD, Associate Professor, Department of Neurology, University of
Wisconsin
Michael E Pitterle MS, Associate Professor, School of Pharmacy, University of Wisconsin
Donna E Cook PharmD, at time of writing, Ambulatory Care Resident, William S
Middleton Veterans Affairs Hospital, Madison, WI; now, Assistant Professor
of Pharmacy, School of Pharmacy, Texas Tech University, Amarillo, TX
Reprints: Barry E Gidal PharmD, School of Pharmacy and Department of Neurology,
University of Wisconsin, 425 N. Charter St., Madison, WI 53706, FAX
608/265-5421, E-mail [email protected]
Funding for this study was provided by Parke-Davis, Morris Plains, NJ.
RESEARCH REPORTS
Downloaded from aop.sagepub.com by guest on October 11, 2013
capsule contents with various food vehicles, may be required.
Indeed, in a recent clinical trial4 evaluating the efficacy
of gabapentin in children, intact capsules were not exclusively
used; capsule contents were also mixed with orange
juice or applesauce. Currently, no parenteral or liquid
formulation of gabapentin exists, and formal pharmacokinetic
studies in the literature have been conducted using
the intact capsule. If this medication is to be used in populations
in which swallowing multiple intact capsules may
be problematic, it is necessary to confirm that drug absorption
is not impaired when alternative methods of administration
are used.
The objective of this study was to evaluate whether significant
(>20%) alterations in absorption occur following
the mixing of gabapentin with food vehicles of differing
macronutrient composition.
Methods
SUBJECTS
Nine healthy adult volunteers with no significant prior medical history
were recruited to participate in this randomized, crossover pharmacokinetic
study. Study subjects consisted of three men and six women,
with a mean ± SD age and weight of 35.5 ± 4.9 years and 71.2 ± 14.8 kg,
respectively. None of the subjects was receiving any concurrent medications
(except for oral contraceptive medication) at the time of the study.
This study was approved by the University of Wisconsin Institutional
Review Board and, prior to study initiation, all subjects provided written
informed consent.
STUDY DESIGN
This study used a single 600-mg dose of gabapentin, given in a randomized,
unblinded, four-way crossover fashion. Foods were selected that
represented common drug administration vehicles. In addition, specific
food vehicle choices were based on reported, product-specific, macronutrient
(i.e., protein, fat, sugar) contents (Table 1). Following an overnight
fast, subjects were asked to take two 300-mg gabapentin capsules (Neurontin,
lot number 06914V) as follows: phase I was the control phase, in
which capsules were swallowed intact with 120 mL of tap water; phase
II, capsules were opened and mixed with 4 oz. of applesauce (Motts);
phase III, capsules were opened and mixed with 120 mL of orange juice
(Citrus Hill); phase IV, the capsules were opened and mixed with 4 oz.
of chocolate pudding (Jell-O, Fat Free). Capsule contents were mixed
thoroughly by the same investigator in the original food containers
(phases II and IV) or in a plastic cup (phase III) immediately prior to ingestion.
Containers were visually inspected to ensure complete ingestion.
Venous blood samples were obtained in nonheparinized tubes from
an antecubital vein at baseline (time 0), and at 0.25, 0.75, 1.0, 1.5, 2.0,
2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, 9.0, and 24.0 hours following drug administration.
Serum was separated by centrifugation, and samples were
frozen at –70 °C until analysis. Subjects were required to remain fasting
(without additional fluids) for 4 hours following drug administration, and
a 1-week washout period separated each study phase, when an identical
program of blood sampling was used.
PHARMACOKINETIC AND STATISTICAL ANALYSIS
Pharmacokinetic variables were calculated by using noncompartmental
techniques and included AUC extrapolated to infinity, maximum
serum concentration (Cmax), and time to maximal serum concentration
(tmax). AUC was determined by using the linear trapezoidal rule. Cmax
and tmax were determined from visual inspection of the graphical data.
Pharmacokinetic variables determined for each study phase were
compared by using ANOVA and the Scheffé post hoc method (SPSS
version 7.0). Additional analyses consisted of subgroup comparison of
relevant pharmacokinetic variables between protein-containing and nonprotein-
containing study phases. For subgroup analysis involving data
sets of differing sample sizes, Student’s t-test for independent data was
used. Statistical significance was assigned at a p value of less than 0.05.
All data are presented as mean ± SD.
LABORATORY ANALYSIS
Serum gabapentin concentrations were determined by using an HPLC
technique as described previously.5 Briefly, this analytical method is a
unique process that uses two solid-phase extractions to achieve selectivity.
The first extraction isolates gabapentin from potentially interfering
compounds such as serum proteins and amino acids. The second extraction
separates the derivatized gabapentin from the derivatizing reagent
and from compounds that may also have been derivatized. Analytical response
was linear from 0.05 to at least 10 μg/mL. The between-run coefficient
of variation was between 2.3% and 2.9%.
Results
PHARMACOKINETIC PARAMETERS
As compared with phase I (control), there were no significant
differences noted in any study arm. Although
mean Cmax and AUC were slightly lower during phase II
(–13.8% and –15.75%, respectively) and phase III (–17.6%
and –15.5%, respectively) compared with the control, these
changes were not statistically significant. The tmax tended
to be quicker (range 0.41–1.4 h) in all study phases compared
with control, but these differences were not statistically
significant. Summary data are presented in Table 2.
Graphical evaluation of phase IV data yielded a seemingly
paradoxical observation, however (Figure 1). Although
not statistically different when all groups are compared
together, an apparent modest increase in both Cmax
and AUC (+18.6% and +13.2%, respectively) was noted in
phase IV compared with the control. Similar to phases II
and III, tmax was also shorter by 1.5 hours compared with
phase I. To further explore these observations, subgroup
analysis was performed between phase IV (protein-containing)
and combined serum concentration data derived in
phases I–III (non-protein-containing phases). In a comparison
of protein versus nonprotein phases, gabapentin AUC
was 26% greater (47.28 ± 14.65 vs. 37.43 ± 9.78 μg/mL•
406 The Annals of Pharmacotherapy 1998 April, Volume 32
Table 1. Food Macronutrient Contents
PROTEIN SUGARS FAT
FOOD (g) (g) (g)
Water 0 0 0
Applesauce 0 18 0
Orange juice 0 12 0
Chocolate pudding 3 17 0
Table 2. Mean ± SD Pharmacokinetic Variables
Cmax tmax AUC
PHASE (μg/mL) (h) (μg/mL•h)
I 3.98 ± 0.69 4.02 ± 1.56 41.79 ± 7.6
II 3.43 ± 0.83 2.61 ± 1.14 35.21 ± 8.7
III 3.28 ± 1.14 3.61 ± 1.43 35.29 ± 12.0
IV 4.72 ± 1.05 2.50 ± 1.09 47.29 ± 14.0
Cmax = maximum serum concentration value; tmax = time to reach Cmax.
h; p = 0.03), and Cmax was 32% higher (4.72 ± 1.04 vs. 3.56
± 0.92 μg/mL; p = 0.003).
Discussion
We evaluated gabapentin pharmacokinetics following
ingestion with several food vehicles. Our observations suggest
that, compared with the ingestion of intact capsules
and water, gabapentin absorption is not significantly impaired
if capsules are opened and mixed with various
foods. This information is clearly relevant in settings
where medications such as antiepileptics must be administered
to patients who are unable to swallow multiple intact
capsules. Our data also suggest that food composition, particularly
protein, may modestly enhance the absorption of
this compound. Specifically, phase IV (chocolate pudding)
was the only food vehicle that contained protein.
Data from previous pharmacokinetic studies evaluating
gabapentin–food interactions have yielded differing results,
depending on experimental design. Ingestion of gabapentin
with a standard, medium-fat breakfast did not result in
significant changes in drug absorption.6 In contrast, concomitant
ingestion with a low-fat, milk-based high-protein
(80 g) breakfast demonstrated a significantly higher Cmax
(36%) compared with the fasted state in 10 healthy subjects.
3 In that study, changes in tmax (–1.1 h) and AUC
(+12.3%) were also of similar direction and magnitude to
values obtained in the low-protein arm of our study. Benetello
et al.7 recently reported findings that seem to confirm
our observations that dietary protein does not impair
gabapentin absorption. Although increases in Cmax following
a high-protein meal were noted, these did not achieve
statistical significance, perhaps reflecting the small sample
size. However, specific information regarding the macronutrient
composition and derivation of the high-protein
meal (i.e., milk vs. meat vs. modular-based protein) or concomitant
fluid intake was not provided in this brief report.
Although the mechanism(s) underlying our present observations
are unclear, several possibilities exist. In addition
to carrier-mediated transport via system L,8 it has been
suggested that passive absorption via paracellular transport,
a property noted for other amino acids, may also occur
with gabapentin.9 Trans-stimulation of carrier-mediated
transport by the increased concentrations of L-amino acids
present in the protein load may also be involved.3 Transstimulation
is a process of adaptive up-regulation, where
the absorptive capacity of the intestinal mucosa can be reversibly
increased following acute increases in intestinal
luminal L-amino acid concentrations.10,11
Of the 3 g of protein, this serving of chocolate pudding
contained 143 mg of L-phenylalanine, 272 mg of L-leucine,
168 mg of L-isoleucine, and 194 mg of L-valine.12 Therefore,
it is possible that the modest, yet statistically significant,
increase in gabapentin Cmax we observed may also be
explained by this phenomenon. It is unclear, however,
whether increases in intestinal luminal concentrations of
unbound amino acids following this small amount of protein
would be sufficient to cause stimulation.13 Alternatively,
alterations in intestinal paracellular transport, the transport
of small hydrophilic drugs through the water-filled
space between epithelial cells, could be involved. It has
been suggested that increasing luminal concentrations of
either amino acids or D-glucose might stimulate an opening
of tight junctions between intestinal epithelial cells, a
process that would induce water and solute absorption
across intestinal mucosa.14
Using a dog model, Stevenson et al.9 recently demonstrated
that following direct jejunal input of a gabapentin
solution, along with an isotonic solution of 50 mM D-glucose,
significant increases in gabapentin AUC were noted.
In this study, no significant changes in either Cmax or tmax
were observed. It may be speculated that the apparent enhancement
of gabapentin plasma concentrations was the
result of glucose-mediated increases in paracellular solvent
drag across the intestinal mucosa. The relevance of these
observations to our study is unclear. Species and experimental
design differences may confound data extrapolation
to in vivo human studies.14 In addition, the monosaccharide
contents of the different food vehicles used in our
study were similar. Interestingly, an unusual concentration
dependence involving both enhancement and inhibition of
gabapentin permeability has recently been demonstrated in
a rat ileum isolated tissue system, suggesting
that the gabapentin carrier can operate in both
directions, perhaps involving differing populations
of transporters (personal communication,
David Fleisher PhD, College of Pharmacy,
University of Michigan, Ann Arbor, MI). In
our study, dietary protein was derived from a
milk-based food. It is unknown whether amino
acids derived from other protein sources
would produce similar results. It is conceivable,
therefore, that both trans-stimulation and
paracellular transport may be involved and are
operative at differing sections of the intestine.
Finally, we have also observed an apparent
change in tmax. An apparent decrease in tmax
was seen in all three groups compared with
phase I; these findings were similar to those
seen when gabapentin was administered with a
high-protein meal.3 It could be hypothesized
Research Reports
The Annals of Pharmacotherapy 1998 April, Volume 32 407
Figure 1. Mean (n = 9) gabapentin serum concentration–time data for study phases I (control)–IV.
that changes in gastric motility between the fasting versus
fed states may help explain the differences seen in tmax
when gabapentin was ingested with a vehicle other than
water. Gastric emptying is delayed by ingestion of food,
which may allow for increased drug dissolution in the
stomach prior to absorption in the small intestine. Delayed
gastric emptying may increase drug absorption by facilitating
longer contact time between the drug and the intestinal
epithelium.15 Our findings, however, showed tmax to be
shorter in the fed versus fasting states, thus implying
quicker absorption when taken with a vehicle other than
water.
Summary
At the doses studied, gabapentin absorption is not significantly
impaired when capsules are opened and mixed
with typical food vehicles, although our sample size may
have precluded the detection of more subtle and less clinically
relevant changes in absorption. Thus, opening capsule
contents in food may be a viable alternative in patients
who are unable to swallow intact capsules. In addition, our
findings tend to support the notion that variation in
macronutrient content (milk-derived protein in particular)
may positively affect gabapentin absorption. It is important
to recognize that, compared solely with control, the pharmacokinetic
changes associated with ingestion of milkbased
protein were modest. Therefore, the clinical significance
of this finding is uncertain. Additionally, the effects
of fluctuating plasma amino acids on the blood–brain barrier
transport of gabapentin have yet to be determined in
patients. Finally, our study was conducted in young,
healthy volunteers. Further studies directed at exploring
and confirming dietary methods to enhance the absorption
profile of this medication in likely target patient populations
(e.g., children, the elderly) would seem reasonable.
Until answers to these important clinical questions are
available, routine attempts at dietary manipulation would
seem premature.
[/I][/I]​

In addition rectal administration provided no benefit in the increase of plasma concentrations of gabapentin.

http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1997.tb01223.x/pdf
 
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