Danny D. Shen

Appointments and Affiliations

 
 
University of Washington
School of Pharmacy
Pharmacy and Pharmaceutics
Professor
University of Washington
School of Pharmacy
Pharmacy
Chair
Fred Hutchinson Cancer Research Center
Clinical Research Division
Biobehavioral Sciences
Pain Research
Full Member
Professional Headshot of Danny D. Shen

Mailing Address

Box 354695
University of Washington
Seattle, Washington 98195-7630
United States

Degrees

Ph.D., State University of New York at Buffalo, Pharmaceutical Sciences, 1975.

Research Interests

Dr. Shen's current research focuses on the preclinical and clinical pharmacology of opioid analgesics, which forms part of the pain research effort within the Biobehaviroal Sciences program in the Clinical Research Division. His current projects cover the following areas:

1) Enhancement of Opioid Analgesia

We have investigated ways to improve the effectiveness of opioid analgesia in patients with chronic sever pain. Our key strategy is to identify drugs that are co-analgesics that would promote analgesic potency of mu-opioid receptor agonists, but do not add to the side effect burden of patients. We have conducted rigorous pharmacodynamic studies in healthy volunteers using well-validated experimental pain paradigms and sophisticated psychometric techniques to fully characterize the subtle, but important, cognitive and psychomotor disturbances induced by opioids. We have demonstrated desirable co-analgesic properties with several serotonergic and GABAergic agents.

2) Pharmacokinetics and pharmacodynamics of spinal opioids.

Spinal opioids are used to treat intractable cancer-related pain with the purported advantage of achieving analgesia through modulation of nociceptive neurotransmission at the spinal cord without incurring systemic side effects. Through laboratory studies in human volunteers, we demonstrated that, following intrathecal or epidural administration, lipolphilic fentanil opioids gain access to the systemic circulation and undergo redistribution to the brain. In fact, the analgesic and side effects of spinally administered fentanil opioids reflect mostly their actions in the brain via redistribution. We have explored through animal studies the use of liposomes to minimize spinal efflux and redistribution of fentanil opioids, and to lengthen their duration of analgesic action. Recently, we demonstrated the role of P-glycoprotein (Pgp) or Multidrug Resistance Related Protein 1 (MDR1) at the capillary endothelium in the delivery of opioids and corticosteroids to the spinal cord.

3) Herb-Opioid Interactions

The Shen Laboratory is currently investigating potentially adverse interactions between herbal supplements and opioid analgesics. Adverse interaction between herb and prescription drug has recently attracted a great deal of public attention. It is becoming a major concern in pain therapeutics. One ongoing project is to investigate possible interactions between the 'natural antidepressant' St. John's wort and two opioids--oxycodone and fentanyl in healthy volunteers. St. John's wort has recently been discovered to have the ability to induce the expression of a key drug metabolizing enzyme, cytochrome P450 3A4 (CYP3A4) and a membrane efflux transporter, P-glycoprotein (Pgp) in the gut and liver. Opioids are known to be substrates for CYP3A4 and Pgp. Hence, upregulation of these two proteins is expected to decrease the intestinal absorption, increase first-pass metabolism in the gut mucosa and the liver, and decrease the bioavailability of opioids. In addition, there is the possibility of inducing the efflux function of Pgp at the blood brain barrier, further hindering the delivery of opioids into the brain.

Additional Experience

1) Cytochrome P450 function in the first-pass metabolism of drugs, 2) transport of anionic drugs (valproic acid) across the blood-brain barrier.

Future Research

Genetic variations in drug-metabolizing enzymes, memebrane transporters and opioid receptors as determinants of inter-patient variability in responsiveness to opioid analgesic therapy.

Industry

My research in opioid metabolism and delivery to the brain and spinal cord is relevant to preclinical development of CNS drug candidates.

Languages

(Reading, Writing, Speaking)

Chinese, Mandarin: (Basic, Basic, Basic)

Memberships

American Association for the Advancement of Science
American Association of Pharmaceutical Scientists
American Pain Society
American Society for Clinical Pharmacology and Therapeutics
American Society for Pharmacology and Experimental Therapeutics
International Association for the Study of Pain
International Society for the Study of Xenobiotics
Society for Neuroscience

Honors and Awards

1995, Fellow, American Association of Pharmaceutical Scientists

 

Recent Publications

2014
2013
Kantor, ED, Ulrich CM, Owen RW, Schmezer P, Neuhouser ML, Lampe JW, Peters U, Shen DD, Vaughan TL, White E.  2013.  Specialty supplement use and biologic measures of oxidative stress and DNA damage.. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Abstract
2012
2010
2009