Excipient excretion

Technetium-99m teboroxime is a myocardial imaging agent and is excreted primarily by the hepatobiliary system. It is rapidly taken up by the myocardium and mosdy washes out within 30 minutes. Imaging protocols are performed immediately after injection. The product is a lyopbili ed mixture of boronic acid, dioxine, and other excipients, and the agent is formed with a beating step. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

Abbreviations. FDA, Food and Drug Administration IPEC, International Pharmaceutical Excipients Council ADME, adsorption, distribution, metabolism, and excretion. 

From 1975 to 1990, scientists at the University of Kansas utilized a rational synthetic design for the definition of a new excipient, the SBE derivative of P-CD (SBE7-P-CD CAPTISOL ). Designing renal safety into the CD was approached by introducing anionic substituents onto the CD structure. This approach capitalized on the increased water solubility that would be realized with the introduction of an ionic substituent. Higher intrinsic water solubility was expected to help minimize the potential precipitation of the CD, if concentrated in the kidney cell, and the charged substituent was expected to capitalize on the ability of the kidney to efficiently excrete ionic compounds into the urine, thus reducing residence time and exposure of the kidney cells to the CD. 

It is conceivable that some excipients may not require the standard 2-year, two rodent species carcinogenicity studies. Such excipients include those that are not absorbed (or are rapidly metabolized and/or rapidly excreted), that do not exhibit toxicity in 90-day studies, and those that are negative for genotoxi-city. This is the approach taken by the IPEC-Americas Safety Committee and one of the reasons that the 1996 peer-reviewed journal publication indicates that the conduct of rodent carcinogenicity studies is conditional. The carcinogenicity studies that are conditional are the traditional 50 animals/sex/group rodent studies conducted for 18 or 24 months or variations thereof. The decision to make these tests conditional was also... 

Study shows that there are no adverse effects after administration of the material at the limit (high) dose generally used in the pharmaceutical industry. An investigative mass, balance, whole-body autoradiography study provides information on absorption, distribution, metabolism, and excretion. This study also involves an investigation of suitable labeling of the material. An in vitro metabolism study (e.g., in rat vs. human hepatocytes) may also be useful for modified food additives and excipients to compare the break-down process and to show possible differences between rat and human in these processes. 

Mannitol is an osmotic diuretic that has been used in acute oliguric renal insufficiency, acute cerebral edema, and the short-term management of glaucoma, especially to reduce intraocular pressure before ophthalmic surgery. Other indications include promotion of the excretion of toxic substances by forced diuresis, bladder irrigation during transurethral resection of the prostate, and oral administration as an osmotic laxative for bowel preparation. Mannitol is used as a diluent and excipient in pharmaceutical formulations and as a bulk sweetener. 

Erythorbic acid is widely used in food applications as an antioxidant. It is also used in oral pharmaceutical applications as an antioxidant. Erythorbic acid is generally regarded as nontoxic and nonirritant when used as an excipient. Erythorbic acid is readily metabolized and does not affect the urinary excretion of ascorbic acid. 

In a smdy of the various physical properties of suppositories, the most important parameter for the bioavailability of paracetamol was found to be their rheological properties at 37°C. The relationship between the excretion of paracetamol (APAP N-acetyl-p-aminophe-nol) and the rheology of the excipient dmg suspension is shown in Fig. 9.55. The greater the limiting shear stress, r, of the system, the lower the bioavailability of the dmg. 

Figure 9.55 Variation of the excretion of APAP (paracetamol) in the urine 2 h after rectal administration of a formulation as a function of the limiting shear stress, z, of the excipient drug-mixture at 37°C.

ARTS Clearance of renally excreted drags, drag-drug, and drag-excipient interactions... 

Like clotrimazole, miconazole was originally developed as an intravenous and oral antifungal agent. The intravenous formulation was discontinued due to anaphylactic reactions associated with the injection vehicle excipient, poly-oxyl 35 Castor Oil (Cremophor EL), used to enhance the solubility of miconazole. Unlike clotrimazole, repeated administration does not induce the hepatic microsomal enzymes involved in its own metabolism. Following oral administration, around 20% of a dose is systemically absorbed where it undergoes oxidadve O-dealkylation and oxidative N-dealkylation prior to excredon (Fig. 24.5). Approximately 40% of the administered dose is excreted unchanged in the faeces. The faecal route of excredon for... 

---