Distribution and Degradation of Two Tritium-Labelled Corticotrophin Analogues in the Rat

Bennett, H. P. J.; McMartin, Colin

doi:10.1677/joe.0.0820033

Cited by 16 publications

(1 citation statement)

References 4 publications

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“…Peptidases are responsible for the rapid inactivation of many small peptides in vivo [6]. It is also clear that each peptide will be inactivated by a small number of these enzymes.…”

Section: Clearancementioning

confidence: 99%

Molecular sieving, receptor processing and peptidolysis as major determinants of peptide pharmacokinetics in vivo

McMartin¹

1989

Biochemical Society Transactions

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Introductory remarks HARlSH M. PATEL I)epirrtr?irrit c)f'Hiochc.rrii.stry, Charirig C'ross arid Westniitister Mcdiiul School, Firlhorn I'alucr Koud, Loridori W6 HKE; U. ti.Peptide and protein drugs have an endogenous origin, are very potent and effective even at a low concentration and produce minimum side-effects. Hence there is a great surge in the rate o f discovery of new drugs, isolation (synthesis) and characterization. Since oral administration of these drugs is not practical because o f degradation and non-absorption in the gastrointestinal tract, the peptides are administered by parenteral routes, which are not very satisfactory since the drugs are degraded at the site of injection and during the hepatic first-pass their therapeutic response is short lived. Thus the current challenge that we face concerns the development o f alternative methods to the painful injection for administration o f these drugs. The routes under investigation involve oral, nasal, colonic, rectal and vaginal mucosa.Oral delivery can be successful if the two major obstacles, enzymic degradation and absorption in the gastrointestinal tract. are overcome. To avoid proteolysis of the peptides in the gut. various approaches are being tried out. These include: co-administration of the peptide with inhibitors of proteolytic enzymes; delivery of the drug t o a site in the gastrointestinal tract where the enzyme activity is minimal; enhancement of absorption of the peptide before proteolysis occurs; encapsulation o f the drug within liposomes; a n d structural modification of the peptide to prevent its proteolysis.The strategies for enhancing absorption of the peptide drugs across the epithelial barrier include co-administration of surfactant, mucolytic agents, etc., modification of peptide structure to increase its lipophilicity and encapsulation of the drug in lipid vesicles. The orally administered peptide is likely to enter the portal circulation and be reduced by hepatic first-pass metabolism. The rectal route, on the other hand, offers a number of advantages over the oral route. These include: reduced proteolytic activity, reduced hepatic first-pass metabolism, low buffer capacity, lymphatic delivery and amenable to adjuvant-enhanced absorption. However, this route may not prove popular with patients.The transdermal route is an attractive alternative, since it offers a number of advantages over oral and nasal routes. It has no serious problems of local proteolytic degradation and hepatic first-pass metabolism and may provide better control of delivery and maintenance of the therapeutic level of drug over a prolonged period of time. This route may prove the most popular with the recipient, since transdermal formulation of peptide drugs can be easily applied to and removed from different parts of the body's skin.Thus there are choices available in the development of alternative routes of administration of peptide drugs, but the formulation of proteins and peptides into effective dosage forms for these routes has become a formidable ta...

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“…Peptidases are responsible for the rapid inactivation of many small peptides in vivo [6]. It is also clear that each peptide will be inactivated by a small number of these enzymes.…”

Section: Clearancementioning

confidence: 99%