L-glutamine has important functions in regulation of gastrointestinal
cell growth, function, and regeneration. Under normal conditions, glutamine
concentration is maintained in the body by dietary intake and synthesis from
endogenous glutamate. Data from clinical studies indicate that the role of and
nutritional requirements for glutamine during catabolic illness, trauma, and
infection may differ significantly from the role of and nutritional requirements
for glutamine in healthy individuals. Glutamine concentrations decrease and
tissue glutamine metabolism increases during many catabolic disease states, and
thus glutamine is often considered a “conditionally essential” amino
When glutamine was administered in combination with recombinant
human growth hormone (rh-GH) to rats, villous height, bowel growth, plasma
insulin-like growth factor I, and body weight were significantly higher than in
animals when either glutamine or rh-GH was administered alone.
The pharmacokinetics of L-glutamine as described below
are based on literature data in healthy subjects. The pharmacokinetics in
patients with short bowel syndrome have not been determined. The plasma glutamine
concentrations in these patients following oral administration are expected to
be highly variable depending on the length, segment, and presence/absence of
ileal-cecal valve for the remnant bowel.
Following single dose oral administration of glutamine at
0.1 g/kg to six subjects, mean peak blood glutamine concentration was 1028 μM
(or 150 μg/mL) occurring approximately 30 minutes after administration.
The pharmacokinetics following multiple oral doses have not been adequately
After an intravenous (IV) bolus dose in three subjects, the
volume of distribution was estimated to be approximately 200 mL/kg.
Endogenous glutamine participates in various metabolic activities,
including the formation of glutamate, and synthesis of proteins, nucleotides,
and amino sugars. Exogenous glutamine is anticipated to undergo similar
Metabolism is the major route of elimination for
glutamine. Although glutamine is eliminated by glomerular filtration, it is
almost completely reabsorbed by the renal tubules. After an IV bolus dose in
three subjects, the terminal half-life of glutamine was approximately 1 hour.
Effect Of Race, Age, And Gender
There are no studies to determine the effect of race, age,
No drug-drug interaction studies have been conducted. Because
metabolism of glutamine is mediated via non- CYP enzymes, glutamine
pharmacokinetics are unlikely to be affected by other agents through CYP enzyme
inhibition or induction.
A randomized, controlled, 3-arm, double-blind,
parallelgroup clinical study evaluated the efficacy and safety of oral
glutamine as a cotherapy with recombinant human growth hormone (rh-GH) in
subjects with short bowel syndrome (SBS) who were dependent on intravenous parenteral
nutrition (IPN) for nutritional support. The primary endpoint was the change in
weekly total IPN volume defined as the sum of the volumes of IPN, supplemental lipid
emulsion (SLE), and intravenous hydration fluid. The secondary endpoints were
the change in weekly IPN caloric content and the change in the frequency of IPN
administration per week.
All subjects received a specialized oral diet (SOD) for
the duration of the study. Following a two-week equilibration period, treatment
was administered in a double blind manner. Group A (N=16) received rh-GH for
four weeks plus oral glutamine placebo for 16 weeks, Group B (N=16) received
rh-GH for four weeks plus oral glutamine for 16 weeks, and Group C (N=9),
received rh-GH placebo for four weeks plus oral glutamine for 16 weeks. The
efficacy of glutamine was assessed by comparing the cotherapy (rh- GH and oral
glutamine) to rh-GH alone.
After 4 weeks of treatment with subcutaneous rh-GH (0.1 mg/kg/d)
and oral glutamine (30 g/d) (Group B), subjects with SBS reduced their
requirement for IPN volume (-7.7 L/wk), IPN caloric content (-5751 kcal/wk),
and weekly frequency of IPN administration (-4.2 d/wk).
Table 1: Results for Endpoints after 4 weeks of
||Group A rhGH + SOD1
||Group B rhGH + SOD[GLN]1
||Group C SOD[GLN]1
|Total IPN volume (L/wk)
|Mean at Baseline
|Total IPN Calories (kcal/wk)
|Mean at Baseline
|Frequency of IPN or SLE (days/wk)
|Mean at Baseline
|1SOD[GLN] = Specialized Oral Diet supplemented
with Glutamine; rhGH + SOD = Human Growth Hormone plus Specialized Oral Diet;
rhGH + SOD[GLN] = Human Growth Hormone plus Specialized Oral Diet supplemented
* p = 0.023, treatment comparison between rhGH + SOD[GLN] versus rhGH+SOD
GROUP A: rh-GH + SOD for 4 weeks followed by SOD for 12 weeks
GROUP B: rh-GH + SOD [GLN] for 4 weeks followed by SOD[GLN] for 12 weeks.
GROUP C: rh-GH placebo + SOD [GLN] for 4 week followed by SOD [GLN] for 12 weeks.
IPN volume requirements were significantly reduced in subjects
receiving subcutaneous rh-GH and oral glutamine (Group B) when compared with
IPN volume requirements in subjects receiving either treatment alone.
Table 2 : Persistence of Treatment Effect
Change in IPN* Volume, Calories, and Frequency Week 2 to Week 18 ITT Population
|Change in weekly IPN Volume (L/wk)
|Change in weekly IPN Calories (kcal/wk)
|Change in weekly IPN frequency (days/wk)
|*IPN is Total IPN excluding supplemental lipid emulsion
(SLE) and hydration fluid.
Group A:rh-GH + SOD for 4 weeks followed by SOD for 12 weeks.
Group B:rh-GH + SOD [GLN] for 4 weeks followed by SOD [GLN] for 12 weeks.
Group C:rh-GH placebo + SOD [GLN] for 4 weeks followed by SOD [GLN] for 12 Weeks
The change in weekly IPN volume, calories and frequency was
assessed from Week 2 to Week 18. The data support that the treatment effect is
maintained for 16 weeks. The efficacy of oral glutamine beyond 16 weeks of
treatment has not been adequately studied.