Small drug molecules, achieved

For a small drug molecule, penetration into the target may often be easier to achieve than duration of action. Assuming duration of action is linked to drug half-life, then distribution as outlined below can be an important factor. 

Small drug molecules have not been extensively researched with microchip electrophoresis devices despite the great potential achieved in conventional CE systems. One reason is that most of the small drug molecules possess chromophores thus, UV absorbance detection is the most popular detection mode but it is not universally available for a microchip device such as LIE is because of sensitivity problems. Because of the radiation danger imposed by UV light, proper instrumental setup specific to the microchip format is required. In addition, UV transparent material such as fused silica or fused quartz is required to fabricate the microchip device. Because UV absorbance is much less sensitive than LIE, a special design is necessary to increase the optical path length of the detection flow cell. This has been achieved by some clever approaches pioneered by Harrison and co-workers.Recently, a commercial microchip electrophoresis system with UV detection was released by Shimadzu, which will drive the application of microanalytical techniques to a wide variety of molecules of pharmaceutical interest. 

Protein precipitation is often used as the initial sample-preparation scheme in the analysis of small drug molecules, since one universal procedure is followed for all compounds and method development is unnecessary. The speed of this technique presents a real time savings. The high resolving power of LC-MS/MS analytical methods accommodates this nonselective cleanup procedure. This mode of sample preparation is also inexpensive and does not chemically alter the analyte. Typical sample matrices that are used with protein-precipitation techniques are plasma, serum, tissue homogenates, and in vitro incubation mixtures. In general terms, a sensitivity of 1-10 ng/mL is often achieved from 50- 4L sample volumes with this technique with LC-MS/MS analysis. 

Ideally, a diffusional implant should be erodible without any adverse effect, and be able to release large or small drug molecules steadily for several months. These two criteria are very difficult to achieve together. However, very few attempts have been made to combine the Type A and B polymers for drug delivery. It is believed that a combined matrix should attenuate somewhat the tissue response to the erosion products from either polymer types, because a lowered amount of one of the compounds in an implant will be required when a second is added. 

In a nnmber of other literature examples, the combination of a desirable in vitro profile with the PK profile reqnired for the development of an oral drug was not achievable. Where the pharmacophores are fundamentally different, it may not be possible to integrate the requirements of both binding sites into a small, compact molecule and a higher MW compound may be unavoidable. Inevitably, this will mean that some combinations of targets will be more difficult, if not impossible, to address with a drug-like molecule, illustrated by example 67 in Figure 27.16. 

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