Drug pump models

Figure 20.7 Multidrug efflux pump. Model of a channel tunnel-dependent export apparatus. Interaction with the adaptor protein opens the entrance of the channel tunnel, allowing export of proteins or drugs. In contrast to the channel tunnel, the structure of the adaptor protein is unknown.

Razel infusion pumps (Model A-99, Razel Scientific, Stamford, CT) provide an easy means to apply drugs via a 10 cc syringe, as described in Subheading 3.2. 

Drug solutions and implantation of osmotic mini-pumps Physostigmine hemisulphate and procyclidine hydrochlorid were obtained from Sigma (St.Louis, U.S.A.), scopolamine hydrobromid from Merck (Darmstadt, Germany), atropine sulphate was obtained from ACF (Amsterdam, The Netherlands), and diazepam from Roche (The Netherlands). HI-6 was made available by the Defence Research Establishment, Suffield, Canada. Soman (O-pinacolyl methylphosphonofluoridate) was synthesised at TNO. Alzet Osmotic Mini-pumps with a constant delivery rate of 0.55 pl/hr (Model 2002, Alza Corp., Palo Alto, USA) were used to deliver PYR, PHY and SCO. The vehicle consisted of 20% propylene glycol, 10% ethanol and 70% water. The pumps were implanted subcutaneously under isoflurane/02 inhalation anesthesia. 

The Sartorius Absorption Model (26), which served as the forerunner to the BCS, simulates concomitant release from the dosage form in the GI tract and absorption of the drug through the lipid barrier. The most important features of Sartorius Absorption Model are the two reservoirs for holding different media at 37°C, a diffusion cell with an artificial lipid barrier of known surface area, and a connecting peristaltic pump which aids the transport of the solution or the media from the reservoir to the compartment of the diffusion cell. The set-up is shown in Figures 7a and b. 

To the donor cell, 3 mL of the model drug solution was added, and to the receptor half-cell 3 mL of the solvent was added. Timing of the diffusion of the solute began as soon as both half-cells were filled. At regular intervals (i.e., 15, 30, and 60 minutes) the contents of the receptor cell were moved and replaced with fresh solvent, which in this case was pH buffer solution. To ensure constant temperature of the iimer cell solution, constant-temperature water was pumped through the outer half-cells. 

This attachment includes model drugs suggested for use in establishing suitability of a permeability method as described in section III. The permeability of these compounds was determined based on data available to the FDA. Potential internal standards (IS) and efflux, pump substrates (ES) are also identified. 

In drug delivery, infusion pumps have achieved remarkable success in recent years. As of 1983, there were 18 different models of external pumps available (6). These battery-powered portable pumps are used to infuse insulin into diabetic patients. Although capable of variable delivery rates, they have a reservoir volume of less than 6 ml, which is unsuitable for fluid replenishment. Further, the cost of these small pumps is very high which limits the affordability to a few selected individuals. 

The irreversible inactivation of endogenous enzymes caused by drugs, e.g., the antiplatelet effect of aspirin after oral administration [442], the 5o-reductase inhibition by a new nonsteroidal inhibitor [443], and the H+, K+-ATPase inactivation by proton pump inhibitors [444], is modeled with turnover models. The simplest model [442] includes terms for the production rate kt and loss rate ka of the response E, coupled with a function g (c) representing the change of plasma or effect-compartment drug concentration ... 

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