Danny D. Shen
Ph.D., State University of New York at Buffalo, Pharmaceutical Sciences, 1975.
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.
1) Cytochrome P450 function in the first-pass metabolism of drugs, 2) transport of anionic drugs (valproic acid) across the blood-brain barrier.
Genetic variations in drug-metabolizing enzymes, memebrane transporters and opioid receptors as determinants of inter-patient variability in responsiveness to opioid analgesic therapy.
My research in opioid metabolism and delivery to the brain and spinal cord is relevant to preclinical development of CNS drug candidates.
(Reading, Writing, Speaking)
Chinese, Mandarin: (Basic, Basic, Basic)
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
Physiological Competition of Brain Phenylalanine Accretion: Initial Pharmacokinetic Analyses of Aminoisobutyric and Methylaminoisobutyric Acids in Pah(enu2-/-) Mice.. Molecular genetics and metabolism reports. 3:80-87.. 2015.
Dexmedetomidine reduces cranial temperature in hypothermic neonatal rats.. Pediatric research. 77(6):772-8.. 2015.
Maternal-Fetal Disposition of Glyburide in Pregnant Mice Is Dependent on Gestational Age.. The Journal of pharmacology and experimental therapeutics.. 2014.
Identification of CYP3A7 for glyburide metabolism in human fetal livers.. Biochemical pharmacology. 92(4):690-700.. 2014.
Aspirin use and knowledge in the community: a population- and health facility based survey for measuring local health system performance.. BMC cardiovascular disorders. 14(1):16.. 2014.
Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport.. Kidney international.. 2013.
Tacrolimus Placental Transfer at Delivery and Neonatal Exposure through Breast Milk.. British journal of clinical pharmacology.. 2013.
Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo.. Toxicology and applied pharmacology. 266(1):122-31.. 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.. 2013.
Innovations in preclinical biology: ex vivo engineering of a human kidney tissue microperfusion system.. Stem cell research & therapy. 4 Suppl 1:S17.. 2013.
Pulmonary Administration of Water-soluble Curcumin Complex Reduces ALI Severity.. American journal of respiratory cell and molecular biology.. 2012.
Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D(3) through CYP3A4 induction in vitro and in vivo: Implications for drug-induced osteomalacia.. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.. 2012.
Interpreting Tacrolimus Concentrations During Pregnancy and Postpartum.. Transplantation.. 2012.
Pharmacokinetics of Tacrolimus During Pregnancy.. Therapeutic drug monitoring. 34(6):660-670.. 2012.
Use of glucosamine and chondroitin in relation to mortality.. European journal of epidemiology. 27(8):593-603.. 2012.
CYP2D6 mediates 4-hydroxylation of clonidine in vitro: implication for pregnancy-induced changes in clonidine clearance.. Drug metabolism and disposition: the biological fate of chemicals. 38(9):1393-6.. 2010.
Effects of Garlic on Cytochromes P450 2C9- and 3A4-Mediated Drug Metabolism in Human Hepatocytes.. Scientia pharmaceutica. 78(3):473-481.. 2010.
Comparative cognitive and subjective side effects of immediate-release oxycodone in healthy middle-aged and older adults.. The journal of pain : official journal of the American Pain Society. 10(10):1038-50.. 2009.
Clonidine pharmacokinetics in pregnancy.. Drug metabolism and disposition: the biological fate of chemicals. 37(4):702-5.. 2009.