Absorption protein drugs

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

VHL Lee, A Yamamoto, U Kompella. (1991). Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. CRC Crit Rev Drug Carrier Sys 8 91-192. 

Wall DA (1995) Pulmonary absorption of peptides and proteins. Drug Debv 2 1-20. 

Subcutaneous and intramuscular Administration Subcutaneous and intramuscular administration can be used to deliver protein-based drugs. The absorption of drug is faster than with the oral route. The rate of absorption is... 

Peptide and protein drugs must be transported without metabolic degradation to the systemic circulation in order to exhibit or exert their pharmacological action. Although active transport of linear peptides and oligopeptides by intestinal oligopeptide transporters has been reported, overall intestinal absorption of peptides is very poor because of metabolic degradation by peptidases. " ... 

Recent years have witnessed an explosive growth in the imderstanding of the mechanisms associated with the absorption of drugs, especially therapeutic peptides and proteins. Scientists from a variety of disciplines continue to elucidate the variables associated with the optimal formulation and delivery of drugs via the oral mucosa. A greater rmderstanding of the para- and transcellular route of drug absorption, pro-... 

Protein-drug Interaction Drug ADME (Absorption, Distribution, Metabolism, and Excretion) Associated Protein Database http //xin.cz3.nus.edu.sg/group/admeap/ admeap.asp Drug ADME-associated proteins... 

Absorption from the intestinal tract is usually good. Food delays but does not reduce absorption. The drug is distributed in body fluids and has a half-Ufe of about 8 hours. High levels are found in plasma and cerebrospinal fluid (CSF). Less than 20% binds to plasma proteins. Metronidazole is metabolized by oxidation and glucuronide formation in the liver and is primarily... 

Rapid and complete absorption (food may decrease absorption) once drug has left stomach. Protein binding 97%. Distributed primarily to gastricparietal cells and converted to two active metabolites. Etxtensively metabolized in the liver. Eliminated in bile and urine. Not removed by hemodialysis. Half-life 1.5 hr (increased in the elderly and in those with hepatic impairment). 

Pharmacokinetics Rapidly and extensively absorbed after PO administration (food decreases drug plasma concentration but doesn t affect absorption). Protein binding 97%, Completely hydrolyzed to active metabolite mycophenolic acid. Primarily excreted in urine. Not removed by hemodialysis. Half-life 17,9 hr. 

Oral drug absorption is nearly complete and concomitant administration of food may decrease the rate, but not the extent of absorption. The drug is 99% bound to plasma proteins and metabolised (1 to 3% of a dose is excreted unchanged in the urine) to several metabolites which are excreted mainly in the urine or the faeces. 

The impact of formulation on protein absorption and disposition is also an important factor in the development and use of biologic molecules. Stability of the protein drug in subcutaneous or muscle tissues and absorption rates directly influence the overall response. Various physical and chemical approaches are used to stabilize proteins and other macromolecules as a part of optimizing dosage formulations. 

Nellans, H.N. 1991. Mechanism of peptide and protein absorption, paracellular intestinal transport Modification of absorption. Adv Drug Deliv Rev 7 339. 

Many drugs can now be delivered rectally instead of by parenteral injection (intravenous route) or oral administration. Generally, the rectal delivery route is particularly suitable for pediatric and elderly patients who experience difficulty ingesting medication or who are unconscious. However, rectal bioavailabilities tend to be lower than the corresponding values of oral administration. The nature of the drug formulation has been shown to be an essential determinant of the rectal absorption profiles. The development of novel absorption enhancers with potential efficacy without mucosal irritation (low toxicity) is very important. The delivery of peptide and protein drugs by the rectal route is currently being explored and seems to be feasible. 

Watanabe, Y., et al. 2000. Absorption enhancement of a protein drug by nitric oxide donor Effect on nasal absorption of human granulocyte colony-stimulating factor. J Drug Target 8 185. 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

Marttin, E., J.C. Verhoef, and F.W. Merkus. 1998. Efficacy, safety and mechanism of cyclodex-trins as absorption enhancers in nasal delivery of peptide and protein drugs. J Drug Target 6 17. 

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