Michael B. Bolger, Ph.D.


Biographical Sketch

Web page updated: 11/5/2006
==================================================

Department Links

Pharmaceutical Sciences
School of Pharmacy

Graduate Curriculum Links

PSCi664 G-Protein Coupled Receptor Handount Fall 2006

Absorption Documents and Spreadsheets

Agoram, Woltosz, and Bolger, "Predicting the Impact of Physiological and Biochemical Processes on Bioavailability", ADDR,50:S41 2001
Download Absorption Simulation Documents

Pharm.D. Curriculum Links

ADMET Predictor and Model Building
GastroPlus and Absorption Simulation

Drug Absorption (Solubility and Permeability)

Therapeutics I (Phar 414) supplement material.
Dose Response Self-study:
Self-Study of Autonomic Pharmacology
Simple Intro. to ANS with hot links to receptor detail
Schematic of ANS with hot links to receptor detail
Cardiovascular Simulation Self-study:

Dietary Approaches to Lowering Cholesterol:

Cyber Patient(TM) and PharmLab(TM) Free Download

Continuing Education Links

Parkinson's Disease Cont. Ed. (accredited CE by AFPE).

Company Links

Michael Bolger dba-LabSoft Solutions
GastroPlus(TM), ADMET Predictor(TM), and ADMET Modeler(TM)



Rational Drug Design and Modeling of Pharmaceutical Targets.

Our goal is to develop novel strategies for therapeutic drug design and testing of small molecules and peptides. The disciplines of chemistry, pharmacology, and molecular biology have been applied to the design, synthesis, and pharmacological testing of agents useful in the treatment of infantile spasms, epilepsy, anxiety, and insomnia. Endogenous hormone metabolites are being modified in order to increase the duration of action, decrease side effects, and maximize efficacy. State of the art techniques in computational chemistry and molecular graphics are applied to all aspects of drug design and modeling of their pharmaceutical targets.

We have developed a novel class of steroidal drugs based on the reduced metabolites of progesterone. These neuroactive steroids are now in clinical trials for infantile spasm and sleep disorders. Our current research is focused on new methods for determination of sub-type selective GABAA receptor allosteric modulators. Sub-type selective allosteric modulators have the potential for more precise control of symptoms without adverse side effects. A novel discovery based on the ability of low level hyperbaric pressure to distinguish agents that act at the neurosteroid site on the GABAA receptor might lead to the development of novel anxiolytics.

Simulation of Drug Absorption and Estimation of ADME Properties

DEVELOPMENT AND VALIDATION OF AN ADVANCED COMPARTMENTAL ABSORPTION AND TRANSIT MODEL - GASTROPLUS(TM) #Simulations Plus, Inc., 1220 W Avenue J, CA 93534.

The ACAT model is based on a measured value for human effective permeability (Peff) and an accurate measure of small intestinal transit time. When coupled to a numerical simulation of seven mixing tank compartments to represent hypothetical compartments of the small intestine, Amidon and co-workers were able to accurately predict Fa. We have now developed a computer simulation program called GastroPlus(TM) that extends the CAT model to include controlled release dosage forms, pH dependence of solubility, and a stochastic propagation of normally distributed Peff values and small intestinal transit times. In addition, we have developed correlations based on calculated logP and molecular weight that can estimate Peff for unknown drugs. The new ACAT model predicted Fa for 37 drugs, with known measured Peff, and found >90% were predicted to have Fa above 85% of their observed Fa or bioavailability. These results can be applied to virtual absorbance screening of unknown molecules.

Selected Publications

  1. Gilman TM, Rose JP, Lipka E, Amidon GL, Woltosz WS, Crison J, Bolger MB. (1999) GastroPLUS(tm) simulated intestinal absorption of drug delivery systems for metoprolol. In: "Proceedings of the 1999 Health Sciences Simulation Conference," Anderson JG, Katzper M, eds., The Society for Computer Simulation International, San Diego, USA, pp. 109-114.

  2. Davies DL, Bolger MB, Brinton RD, Finn DA, and Alkana RL. (1999) In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol. Psychopharmacology, 141:339-350 (1999).

  3. Bolger MB, Haworth IS, Yeung AK, Ann D, Grafenstein HV, Hamm-Alvarez S, Okamoto CT, Kim KJ, Basu SK, Wu S, and Lee VHL. (1998) Structure, Function, and Molecular Modeling Approaches to the Study of the Intestinal Dipeptide Transporter PepT1. J. Pharm. Sci. 87(11):1286-1291.

  4. Haworth IS, Bolger MB, and Eriksen SP. (1997) The use of computer-based case studies in a problem-solving curriculum. Am. J. Pharm. Ed. 61(1):97-102.

  5. Bolger MB and Haworth IS. (1997) PharmLabTM: A computer program for the calculation and visualization of drug degradation pH rate profiles. Am. J. Pharm. Ed. 61(3):281-287.

  6. Carter RB, Wood PL, Wieland S, Belelli D, Lambert JJ, White HS, Tahir H, Bolger MB, Lan NC, and Gee KW. (1997) Characterization of the anticonvulsant properties of Ganaxolone (CCD 1042; 3a-hydroxy-3b-methyl-5a-pregnan-20-one), a selective high-affinity steroid modulator of the GABAA receptor. J. Pharm. Exp. Ther. 280(3):1284-1289.

  7. Hogenkamp DJ, Tahir SH, Hawkinson JE, Upasani RB, Alauddin M, Kimbrough CL, Acosta-Burruel M, Whittenmore ER, Woodward RM, Lan NC, Gee KW, and Bolger MB. (1997) Synthesis and in vitro activity of 3b-substituted-3a-hydroxypregnan-20-ones: Allosteric modulators of the GABAA receptor. J. Med. Chem. 40:61-72.

  8. Bolger MB, Wieland S, Hawkinson J, Xia H, Upasani R, and Lan NC. In vitro and in vivo activity of 16, 17-dehydro-epipregnanolones: 17, 20-Bond torsional energy analysis and D-ring conformation. Pharm Res, 13(10):1488-1493, 1996.

  9. Bolger MB and Basu S. (In: A Critical Assessment of Comparative Molecular Modeling of Tertiary Structures of Proteins, by Mosimann S, Melesko, R, and James, NG). Proteins: Structure, Function, and Genetics, 23:301-317, 1995)

  10. Bolger M.B. Computational Techniques in Macromolecular Structural Analysis. With diskette supplement to chapter. (1995) Chapter 9 in "Introduction to Biophysical Methods for Protein and Nucleic Acid Research", Ed. Deutscher M, and Glasel JA), Academic Press, San Diego: 433-490.

  11. Bolger MB, Gee KW, Lan N, Belelli D, Mirsadeghi S, Purdy R, and Tahir H. Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series. US Patent 5,232,917 Issued August 3, 1993.

  12. Lan NC, Bolger MB, Gee KW: (1991) Identification and Characterization of a Pregnane Steroid Recognition Site that is Functionally Coupled to an Expressed GABAA Receptor. Neurochem. Research 16:347-356 (1991)

    You can E-mail me at: bolger@usc.edu