Principles of Clinical Pharmacology 2001-2002

Lecture 16. January 10, 2002

Module 2. Drug Metabolism and Transport

Unit 6. Equilibrative and Concentrative Transport

Peter C. Preusch, NIGMS

Please refer to [Principles of Clinical Pharmacology]{.underline},
Chapter 16 for the majority of the lecture references. The following
updates are mentioned in this year\'s lecture.

**Paracellular Transport and Permeation Enhancers**

Ward PD, Tippin TK, Thakker DR. Enhancing paracellular permeability by
modulating epithelial tight junctions. Pharmaceutical Science and
Technology Today 2000, 346-358.

Thanou M, Florea BI, Langemeyer MW, Verhoef JC, Juninger HE.
N-trimethylated chitosan chloride (TMC) improves the intestinal
permeation of the peptide drug buserelin in vitro (Caco-2 cells) and in
vivo (rats). Pharm Res 2000 Jan; 17(1):27-31.

**Endocytosis and Transcytosis Pathways:**

Mostov KE, Verges M, Altschuler Y. Membrane traffic in polarized
epithelial cells. Curr Opin Cell Biol. 2000 Aug;12(4):483-90. Review.

Mellman I. Endocytosis and molecular sorting. Annu Rev Cell Dev Biol.
1996;12:575-625. Review.

Hussain N, Jani PU, Florence AT. Enhanced oral uptake of tomato
lectin-conjugated nanoparticles in the rat. Pharm Res. 1997
May;14(5):613-8.

**VitB12 receptor** - facilitates GI uptake of VitB12 bound to intrinsic
factor binding protein. Biotech Australia LTD is developing this for
drug delivery.

Russell-Jones GJ. The potential use of receptor-mediated endocytosis for
oral drug delivery. Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):59-73. Review

Alsenz J, Russell-Jones GJ, Westwood S, Levet-Trafit B, de Smidt PC.
Oral absorption of peptides through the cobalamin (vitamin B12) pathway
in the rat intestine. Pharm Res. 2000 Jul;17(7):825-32.

Russell-Jones GJ. Use of vitamin B12 conjugates to deliver protein drugs
by the oral route. Crit Rev Ther Drug Carrier Syst. 1998;15(6):557-86.
Review.

**Neonatal Fc Receptor (FcRn)** - MHC protein that facilitates uptake of
antibodies from colosrum/milk.. Syntonix Pharmaceuticals, Inc. (Waltham,
MA) is developing. See: www.syntnx.com. XenoPort, Inc. (Palo Alto) is
also developing. See: www.xenoport.com.

McCarthy KM, Yoong Y, Simister NE. Bidirectional transcytosis of IgG by
the rat neonatal Fc receptor expressed in a rat kidney cell line: a
system to study protein transport across epithelia. J Cell Sci. 2000
Apr;113 ( Pt 7):1277-85.

Ghetie V, Ward ES. Multiple roles for the major histocompatibility
complex class I- related receptor FcRn. Annu Rev Immunol.
2000;18:739-66. Review.

Israel EJ, Taylor S, Wu Z, Mizoguchi E, Blumberg RS, Bhan A, Simister
NE. Expression of the neonatal Fc receptor, FcRn, on human intestinal
epithelial cells. Immunology. 1997 Sep;92(1):69-74.

**Polymeric immunoglobulin receptor (PigR)** - facilitates transport
serosal to mucosal of IgA and IgM. AriZeke Pharmaceuticals, Inc. (San
Diego) is developing this approach.

Apodaca G, Mostov KE. Transcytosis of placental alkaline
phosphatase-polymeric immunoglobulin receptor fusion proteins is
regulated by mutations of Ser664. J Biol Chem. 1993 Nov
5;268(31):23712-9.

**Computer Predictions of Permeability**

GastroPlus software from Simulations Plus, Inc., developed in
collaboration between Gordon Amidon (Univ. Michigan and Therapeutic
Systems Research Laboratories \[TSRL\], Inc.) and Michael B. Bolger
(Univ. Southern California and Simulations Plus, Inc, Lancaster, CA).
See: http://www.simulations-plus.com.

Reports avail: \"Computational Methods to Predict Biopharmaceutical
Properties\", Michael B. Bolger, AAPS, Meeting, Indiannapolis, Oct
29-Nov 2, 2000. PDF.

http://www.simulations-plus.com/pdf_files/aaps_2000_report.pdf

Includes two major products:

QMPRPlus predicts Quantitive Molecular Property Relationships from
structures using neural network models trained for several hundred to a
few thousand real compounds.

GastroPlus uses calculated or experimental QMPR data to predict ADME
characteristics using Advanced Compartmental Absorption and Transit
models of the GI tract.

**Structural Biology of Membrane Proteins Landmark**

Chang G and Roth CB. Structure of MsbA from E. coli: A Homolog of the
Multidrug Resistance ATP Binding Cassette (ABC) Transporters. Science
Sep 7 2001: 1793-1800.

\- first complete high resolution x-ray crystallographic structure of
any ABC transporter.

Steven White\'s Website - a useful resource on membrane protein
structure and topology.

See: http://blanco.biomol.uci.edu/mptopo/

**Pharmacogenetics/Pharmacogenomics**

NIGMS Funded Pharmacogenetics Network and Knowledge Base

http://www.pharmgkb.org

UCSF contribution to Pharmacogenetics Network. Project focused on
transporters.

http://pharmacogenetics.ucsf.edu

Human Membrane Transporter Database: A Web-Accessible Relational
Database for Drug Transport Studies and Pharmacogenomics. Q. Yan, W.
Sadée. [AAPS PharmSci](http://www.pharmsci.org/) 2(3): article 20 (2000)
(<http://www.pharmsci.org/scientificjournals/pharmsci/journal/20.html>).

<http://lab.digibench.net/transporter/>)

The SNP Consortium Ltd. Search \"transport\" =\>29 in April, but 58 on
12/28/01.

http://snp.cshl.org/db/searches/text/snp

Division of Gastroenterology and Hepatology, Univ. Groningen, Prof.
P.L.M. Jansen, Head. http://www.med.rug.nl/mdl/index.htm.

Site includes data on transporter proteins, promotors of transporter
genes, other interesting information. The Human ABC Transporters Page -
claims there are 51 to be found and identifies most. The Transporter
Page - includes lists of Solute Carrier Family SCF10, SCF21, SCF22, as
well as ABC family transporters. Hepatic Transporters an Diseases
related to Transporter Dysfunction.