Other Routes of Protein and Peptide Delivery: Transdermal, Topical, Uterine, and Rectal - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 647

and vaginal are used. Conjunctival and transdermal routes are being investigated.
Rectal administration may potentially be an important route for peptide administra-
tion, although among available options it is poorly accepted by patients. In contrast to
the oral route of administration, the rectal delivery of peptide and protein drugs pro-
vides the advantage of greater systemic bioavailability, especially with the coadmin-
istration of adjuvant. An additional advantage is that it avoids first-pass elimination.
However, the rectal absorption of peptide and protein drugs is still poor as compared
with intravenous administration. Consequently, various approaches have been exam-
ined to improve the absorption of these drugs from the intestine, including the rec-
tum. However, it is generally agreed that absorption enhancers are required to achieve
therapeutic plasma levels of rectally dosed peptides.
12.4.2 Rectal Absorption
The rectal route is extremely useful for delivery of drugs to newborn and young chil-
dren. Disadvantages are limited surface area, dissolution problems, and interruption of
drug absorption during defecation and inconsistent patient acceptability. However, the
rectal route does offer a more convenient way to control drug release, using osmotic
pumps and hydrogel cylinders, although to date they have only been tested with low-
molecular-weight drugs, such as propranolol [159] and nifedipine [160,161] .
Traditionally, the rectum has been an accepted site of drug delivery. Its principal
applications have been for local therapy, for example, for hemorrhoids, and for sys-
temic delivery of drugs to groups presenting practical problems for parenteral or oral
dosing to patients such as infants and epileptics. Some populations are less willing
to accept this route as a standard method for drug delivery, but it is the most easily
accessible area of the lower GI tract. As such, it offers the potential for delivery of
peptides without the need for targeted devices, and its efficiency is simpler to test
in vivo in both animals and humans. However, it is generally agreed that absorption
enhancers are needed to achieve therapeutic plasma levels of rectally dosed peptides.
Many groups have looked at the bioavailability of a variety of peptides in the rat
after rectal administration. Mikaye et al. [162] and Morimoto et al . [163] detected
low levels of absorption of [Asu 1,7]-eel calcitonin (MW 3415) after rectal admin-
istration to rats. Hypoglycemic response was detectable only in the presence of an
enhancer. Rectal absorption of desglycinamide arginine vasopressin (dGAVP, MW
1100) has been investigated by van Hoogdalem et al. [164] . Negligible bioavailability
with dGAVP was observed, but with sodium tauro-24,25-dihydrofusidate (STDHF),
which is an absorption enhancer, a bioavailability of 27  6% was observed. After
rectal administration of insulin (MW 5800), it was demonstrated a bioavailability of
0.2  0.2%, increasing to 4.2  3.2% and 6.7  2.1% following coadministration
of different doses of STDHF [165] . The significance of absorption from the rectum
into the lymphatic system has been investigated by Yoshikawa et al. [166] . They have
demonstrated that negligible levels of human -interferon (MW 17,000) in serum
and plasma were detected after rectal administration. Coadministered mixed micelles
attained selective lymphatic uptake. These data indicate that rectal absorption of even
large peptides is feasible. The generally low bioavailability by simple rectal absorption