Epilepsia, 38( I I ): 1242-1244, 1997
Lippincott—Raven Publishers, Philadelphia
(3 International League Against Epilepsy
Brief Communication
Failure of Absorption of Gabapentin After Rectal Administration
*`*Robert L. Kriel, *Angela K. Birnbaum, *James C. Cloyd, §Beverly J. Ricker,
*Carolyn Jones Saete, and *Kimberly J. Caruso
Departments of Pediatrics and Neurology, *Gillette Children's Specialty Healthcare and Hennepin County Medical Center;
*College of Pharmacy, University of Minnesota, and §Edina Pediatrics, Minneapolis, Minnesota, U.S.A.
Summary: Purpose: We wished to determine the extent of
absorption of gabapentin (GBP) after rectal administration to
children on maintenance therapy.
Methods: Two children scheduled for extensive surgery re-
ceived GBP rectally and orally. A pharmacokinetic profile was
derived after each route of administration.
Results: Serum GBP levels after rectal administration de-
creased at a rate similar to their rate of decrease after oral
administration. However, GBP concentrations were much
lower after rectal administration; therefore, we concluded that
Gabapentin (GBP) is a new antiepileptic drug (AED)
that has been approved for adjunctive treatment of partial
and secondarily generalized seizures in patients aged
12 years. Several reports describe the use and adverse
effects of GBP in children (1-4) although systematic
pharmacokinetic studies either are still in progress or
have not been published. Although GBP is soluble in
water, neither oral liquid nor parenteral formulations are
available. The drug is absorbed by an active transport
process and is eliminated unchanged by the kidney (5).
In numerous circumstances, oral administration of
medication is impossible, particularly in children. Ex-
amples of these include gastrointestinal infections with
vomiting, intestinal dysfunction after abdominal surgery,
fasting states prior to administration of anesthesia, and
times of severe impairment of consciousness. During
such episodes, physicians caring for children often ad-
minister medications rectally if parenteral formulations
are unavailable (6). Because use of GBP in children is
increasing, clinicians will undoubtedly encounter situa-
tions in which oral therapy will be interrupted. There -
Accepted July 10, 1997,
Address correspondence and reprint requests to Dr. R. L. Kriel at
Hennepin County Medical Center, #867B, 701 Park Ave. S., Minne-
apolis, MN 55415, U.S.A. fore, we wished to determine
whether GBP is absorbed after rectal administration.
1242
the aqueous solution was poorly absorbed rectally. The GBP
half-life (t1/2) for the 2 children after oral doses were 4.2 and
4.8 h.
Conclusions: Rectal administration of GBP is not satisfac-
tory when oral administration is interrupted. When oral GBP
therapy is temporarily discontinued, clinicians should consider
administration of alternative antiepileptic drugs (AEDs) that
can be administered parenterally or rectally. Key Words:
Gabapentin—Rectal—Bioavailability.
METHODS
Our study was designed to characterize the pharmaco-
kinetics of GBP after oral and rectal doses administered
to 6 children. Because we hypothesized that GBP would
be poorly absorbed after rectal administration, we
planned an interim analysis after completing studies in 2
children. Absorption after rectal administration was so
poor that we terminated the study after treating the first
2 children.
Families of children scheduled for major surgery who
were expected to be unable to take anything by mouth for
a substantial time period were asked to permit their
child's participation in the study. The investigation was
approved by the Human Subjects Committees of Henne-
pin County Medical Center, Gillette Children's Specialty
Healthcare, and the University of Minnesota; informed
consents were obtained from parents or legal guardians.
The investigations were made several weeks before the
scheduled surgery.
For 1 day prior to each study, the patients were re -
quested to take the usual total daily GBP dose, admin-
istered as evenly divided doses every 8 (patient 1) or
 RECTAL ABSORPTION OF GBP
every 6 (patient 2) h. The children were observed for 8 h
in an inpatient setting. Both subjects received a single
oral and a single rectal dose. Patient 1 was initially stud-
ied after the oral dose and patient 2 was initially studied
after the rectal dose. Patient 1 usually receives GBP as
the intact capsule; for patient 2, has GBP is suspended in
water and administered through a feeding tube. Patient
1, a 12-year old girl weighing 25 kg, was receiving
GBP 300 mg/day orally three times daily. For the study,
she received 200 mg GBP orally and blood samples
were taken (Fig. 1). Four days later, she received the
same dose rectally.
Patient 2, a 15-year-old boy weighing 31 kg, was re-
ceiving GBP 800 mg/day through a feeding tube four
times daily. On study day 1, he was administered 200 mg
GBP rectally. The oral dose was administered on the
following day. For oral administration, GBP capsules
were opened and 200 mg GBP powder was added to 5 ml
tap water; the mixture was administered with food to the
patient through his feeding tube.
At the conclusion of the study, the children resumed
their usual dosing schedule and were discharged from the
hospital. Results of the serum assays were made avail-
able to the treating neurologists and families before the
scheduled surgery so that management decisions con-
cerning antiepileptic drug (AED) therapy could be made
for the time when medications could not be administered
orally.
Preparation for rectal administration
For each patient, the rectal dose was prepared by open-
ing the GBP capsules and emptying their contents into 5
ml warm tap water. The solution was drawn into a sy-
ringe and inverted four or five times before being in-
Patient
FIG. 1. Oral versus rectal admin-
istration of gabapentin. The oral
predose blood sample of patient 1
could not be measured because
of an assay error and because the
quantity was insufficient to allow
the assay to be repeated. Plotting
of this graph assumes that the CS
rectal and oral predoses were the
same. The pharmacokinetic cal-
culations were not affected since
the dose was in the preabsorption
portion of the area under the se- Oi 2 3 4 8
rum concentration—time curve. Time After Dose (hrs)
1112(oral).=4.8hrs
t112(rectal) =8.8 hrs
Relative bioavailabifity=0.29
1243
stilled rectally. The patients were placed in a right lateral
decubitus position and, with a 5-ml syringe without an
attached catheter, the GBP/tap water mixture was in-
serted 2.5 inches into the rectum and administered in a
1-min period. After drug administration, the patients
rested supine for at least 60 min and were observed to
ensure that there was no rectal expulsion of the drug
during that time.
To verify that GBP prepared in this manner was
soluble and stable, we assayed GBP mixtures so pre-
pared. Analysis showed that the mixtures contained an
average of 97% GBP. All serum GBP concentrations
were measured by high-performance liquid chromatog-
raphy (HPLC, MEDTOX Laboratories, St. Paul, MN,
U.S.A.).
Pharmacokinetic analysis
We constructed area under the serum concentration—
time curves (AUCs) over the dosing interval, using the
trapezoidal rule for both oral and rectal doses. We cor-
rected the AUCs for the contribution of prior doses by
dividing the pre-dose concentration by the elimination
rate constant. Time to maximum concentration (T.)
was determined from visual inspection of the concentra-
tion—time plots. Elimination rate constants (ke) were de-
termined from the slope of the regression line containing
the postabsorption concentrations. Elimination half-life
(t1/2) was calculated as follows: t1/2 = 0.693/ke. Because
no intravenous GBP formulation is available, absolute
bioavailability could not be measured. Therefore, we de-
termined the relative bioavailability of rectally adminis-
tered GBP by comparing the ratio of the AUCs for the
rectal and oral doses (7).
Patient 2
8 + i v
Time After Dose (hrs)
1112 (oral) = 4.2 hrs
t1/2(rectal) = 4.5 hrs
Relative bloavailabiltty = 0.17
Epilepsia, Vol. 38, No. 11, 1997
1244 R. L. KRIEL ET AL.
RESULTS
Serum concentrations of GBP after oral and rectal ad-
ministration are shown in Fig. 1. The relative bioavail-
abilities of rectally administered GBP in our 2 patients
were 0.29 and 0.17. No increase in concentration was
observed in either child after rectal administration. In-
stead, a steady decrease from the trough predose level
paralleled the postabsorption decrease after oral admin-
istration. Therefore, we conclude that there was no mea-
surable absorption of GBP after rectal administration.
Inspection of the curve showed that T. values after the
oral dose of GBP occurred at 1 and 4 h. Elimination t1/2
was derived both after oral and rectal doses, assuming no
absorption after the rectal dose and continued elimina-
tion after the last oral dose.
No adverse effects were observed after either route of
administration. No change in seizure frequency or sever-
ity was reported during or immediately after the inves-
tigations.
DISCUSSION
We expected that absorption of GBP after rectal ad-
ministration would be poor. Drugs best absorbed rectally
are those that are lipophilic and nonionized at physi-
ological pH (6). GBP is water soluble, is ionized at
physiological pH values, and is absorbed from the small
intestine by an active transport mechanism (5). Failure of
GBP absorption could be due to poor water solubility,
poor stability, decreased rectal surface area, or the ab-
sence of an active transport system. GBP was both
soluble and stable when prepared for rectal administra-
tion (described in the Methods section). The rectal cavity
has 1/10,000 of the surface area of the small intestine,
and whether rectal mucosa possesses the L-leucine amino
acid transport system utilized for GBP transport is not
known (8,9). Because of the greatly reduced surface area
of the rectum, the saturation of absorptive capacity that
occurs even in the small intestine would be more exag-
gerated in the rectum even if the transport system ex-
isted.
Although the data we obtained after administering oral
doses of GBP in our 2 patients are limited, they are the
first pharmacokinetic data obtained in children to be pub-
lished. The serum GBP concentrations observed in the 2
Epilepsia, Vol. 38, No. 11, 1997
children after oral doses are similar to those reported for
adults receiving equivalent doses in milligrams per kilo-
gram. The elimination t1/2 was at or below the lower
range observed in adults. Future studies in children are
necessary to determine whether GBP should be admin-
istered more frequently and at higher doses to attain tar-
geted concentrations.
GBP is poorly absorbed after rectal administration of
a GBP aqueous solution. Unfortunately, because no for-
mulation of GBP is suitable for either parenteral or rectal
administration, clinicians must offer alternative therapy
when GBP cannot be administered orally. The usual
choices obviously are the AEDs that can be administered
parenterally. Alternatively, drugs that are absorbed after
rectal administration, such as valproate and carbamaze-
pine can be administered (10,11). As soon as a patient
can again tolerate oral administration, use of oral GBP
treatment should be resumed.
Acknowledgment: This work was supported in part by the
Minneapolis Medical Research Foundation of Hennepin
County Medical Center.
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