Pharmacogenetics of Intestinal Absorption

Author(s):

Tsutomu Nakamura, Motohiro Yamamori and Toshiyuki SakaedaPages 153-169 (17)

Abstract:

The small intestine is the primary site of absorption for many drugs administered orally and so is the target tissue for pharmacotherapeutic strategies to control the oral absorption of drugs. Drug transporters, including the ATP-binding cassette (ABC) superfamily and the solute carrier (SLC) superfamily, have been considered to play a physiological role in regulating the absorption of xenobiotics, and variations in their expression level and function in the small intestine cause intra- and inter-individual variation in the oral absorption of drugs. Recent advances in molecular biology have suggested that genetic polymorphisms are associated with the expression level and function, and thereby inter-individual variation. In this review, the pharmacogenetics of these transporters is summarized, and their future significance in the clinical setting is discussed.

Affiliation:

Department of Clinical Evaluation of Pharmacotherapy, Kobe University Graduate School of Medicine,Kobe 650-0047, Japan.

Read Full-Text article

Read More

Enhanced Delivery of Topically-Applied Formulations Following Skin Pre-Treatment with a Hand-Applied, Plastic Microneedle Array

Author(s):

Dan Duan, Craig Moeckly, Jerry Gysbers, Chris Novak, Gayatri Prochnow, Kris Siebenaler, Leila Albers and Kris HansenPages 557-565 (9)

Abstract:

The purpose of this work is to characterize microchannels created by polymeric microneedles, applied by hand, and to demonstrate enhanced delivery of topically applied formulations of lidocaine hydrochloride and methylprednisolone sodium succinate (MPSS). 3Ms Microstructured Transdermal System (MTS) arrays were applied to domestic swine to demonstrate reliability of penetration, depth of penetration and durability of the structures to repeat application and high force. Tissue levels of lidocaine and MPSS following topical application with and without microneedle pretreatment were determined by HPLC-MS analysis following digestion of biopsies. Almost all microneedles penetrate the stratum corneum upon hand force application. The depth of penetration varies from < 100μm to nearly 150μm depending on the application force and the firmness of the underlying tissue. The arrays show excellent durability to repeated in-vivo application, with less than 5% of the structures evidencing even minimal tip bending after 16 applications. Under extreme force against a rigid surface, the microneedles bend but do not break. A lidocaine hydrochloride formulation applied topically in-vivo showed ∼340% increase in local tissue levels when the MTS arrays were used to twice pre-treat the skin prior to applying the drug. Local delivery of a topically applied formulation of MPSS was over one order of magnitude higher when the application site was twice pre-treated with the MTS array. 3Ms MTS array (marketed as 3M™ Microchannel Skin System) provides repeatable and robust penetration of the stratum corneum and epidermis and enhances delivery of some formulations such as lidocaine hydrochloride.

Keywords:

Dermis, epidermis, stratum corneum penetration, microneedles, microporation, dermal, stratum corneum, lidocaine, absorption, drug delivery, transdermal, skin

Affiliation:

3M Drug Delivery Systems Division, Building 260-03-A-05, St. Paul MN 55114, USA.

Read Full-Text article

Read More

Anatomical and Histological Factors Affecting Intranasal Drug and Vaccine Delivery

Author(s):

Sveinbjorn GizurarsonPages 566-582 (17)

Abstract:

The aim of this review is to provide an understanding of the anatomical and histological structure of the nasal cavity, which is important for nasal drug and vaccine delivery as well as the development of new devices. The surface area of the nasal cavity is about 160 cm2, or 96 m2 if the microvilli are included. The olfactory region, however, is only about 5 cm2 (0.3 m2 including the microvilli). There are 6 arterial branches that serve the nasal cavity, making this region a very attractive route for drug administration. The blood flow into the nasal region is slightly more than reabsorbed back into the nasal veins, but the excess will drain into the lymph vessels, making this region a very attractive route for vaccine delivery. Many of the side effects seen following intranasal administration are caused by some of the 6 nerves that serve the nasal cavity. The 5th cranial nerve (trigeminus nerve) is responsible for sensing pain and irritation following nasal administration but the 7th cranial nerve (facial nerve) will respond to such irritation by stimulating glands and cause facial expressions in the subject. The first cranial nerve (olfactory nerve), however, is the target when direct absorption into the brain is the goal, since this is the only site in our body where the central nervous system is directly expressed on the mucosal surface. The nasal mucosa contains 7 cell types and 4 types of glands. Four types of cells and 2 types of glands are located in the respiratory region but 6 cell types and 2 types of glands are found in the olfactory region.

Keywords:

Drug delivery, intranasal administration, nasal administration, nasal anatomy, nasal cavity, nasal device, nasal histology, vaccine delivery

Affiliation:

Faculty of Pharmaceutical Sciences, University of Iceland, Hofsvallagata 53, 107 Reykjavik, Iceland.

Read Full-Text article

Read More

Temporal Separation in the Release of Bioactive Molecules from a Moldable Calcium Sulfate Bone Graft Substitute

Author(s):

Matt E. Brown, Yuan Zou, R. Peyyala, Thomas D. Dziubla and David A. PuleoPages 605-612 (8)

Abstract:

Treatment of infected bone defects presents a considerable challenge due to the complications that occur from significant bone damage concomitant with contaminated tissue. These wounds are most often treated in a two-step sequence, where the infection is first eliminated before any attempt to repair the bone is undertaken. In order to combine these two treatment steps into one procedure, a moldable bone grafting material was developed to deliver drugs in a temporally separated manner. This was accomplished by a two-layered calcium sulfate composite consisting of a moldable outer shell containing antibiotic-loaded poly(lactic-co-glycolic acid) microspheres wrapped around a preformed core containing an osteogenic drug. The release of vancomycin from the shell portion began immediately and continued over the course of 6 weeks, while the release of simvastatin from the core was delayed for 12 days before being released over the next 4 weeks. Bioactivity of vancomycin was shown in modified Kirby-Bauer experiments in which whole samples inhibited Staphylococcus aureus (S. aureus) growth for 2 weeks. This two-layered system is capable of delivering antibiotics locally for clinically relevant periods of time and delaying the release of osteogenic drugs to mimic a two-step procedure that has potential for treating infected bone defects.

Keywords:

Bone filler, bone graft substitute, calcium sulfate, composite, moldable, sequential release, simvastatin, vancomycin.

Affiliation:

522A Robotics and Manufacturing Building, Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40506-0108, USA.

Graphical Abstract:

Read Full-Text article

Read More