1. Pyoderma gangrenosum: the hazards of polypharmacy in patients with impaired clearance mechanisms Ashley Fletcher, Colleen Reisz UMKC School of Medicine Introduction Pyoderma gangrenosum (PG) is a devastating ulcerative skin disease. It typically occurs on the lower legs in the setting of debility, impaired clearance mechanisms and polypharmacy. Inflammatory bowel disease as the most frequent co-morbidity. 1 Bile acid (BA) metabolism is controlled by receptors that have dual functions in drug metabolism. Farnesoid X, (FXR) the nuclear receptor that regulates bile acid synthesis, directly affects drug transport at the intestinal lumen. 2 We theorized that the uncontrolled pathergy seen in PG was related to compromised endo and xenobiotic clearance in patients with polypharmacy. Debilitated patients with compromised clearance mechanisms at the intestinal lumen, liver or kidney often have the dual burden of polypharmacy. Improvement in pathergy may be facilitated by drug reduction. Methods. This is a case series of 13 female patients with PG. We included biometric data, comorbid states, Fitzpatrick phototyping, and drug lists. Drug reduction strategies included cessation of specific drugs, dose reduction, increase in dosing interval, class switch or selection of another drug within class. Vitamins and supplements were removed except for vitamin D and renal vitamins in patients with renal failure. Danazol, an androgen with fibrinolytic effects, was added to those with a known hypercoag disorder. ResultsSummary FXR is the link between xenobiotic sensing and BA regulation. Control of BA metabolism is essential for clearance of toxic bile acid salts. The nuclear receptors that control BA metabolism have dual function in drug clearance FXR is the central receptor in hepatoprotection from BA toxicity and has been shown to activate transcription of the PXR gene, providing the mechanism by which FXR protects the liver from the toxic effects of excess BA. 4.FXRα is expressed in the liver, kidney, intestine and and renal cortex. 4 FXR-dependent hepatoprotection also involves the induction of proteins involved in transporting bile acids and phospholipids into the bile, including multidrug resistant protein 2. 4 FXR induces the expression of BSEP (ABCB11), a major canalicular bile salt export pump, which belongs to the family of ATP-binding cassette (ABC) transporters. This transporter class is on the apical surface of the intestinal lumen. 5 Alterations in BA production and transporter activity change drug metabolism and activity. The application of this information is underutilized in patients with complex medical situations and polypharmacy, such as those found in patients with PG. Limitations: This is a small case series of women with PG and the clinical results are not generalizable. They had received many different treatments for their skin disease, including steroids, immune suppressants, and locally applied therapies from wound care clinics. Conclusions are theorized because there is no hard evidence or tests to confirm. Conclusion PG may arise in patients with aberrant molecular communication between bile and drug metabolism. The initial evaluation of patients with PG should include a careful medication history, specifically targeting drugs that impact cholesterol metabolism, BA formation and steroidogenesis. Reduction of polypharmacy should be given the highest priority. This will require a coordinated approach that seeks input from all caregivers. References 1.Powell FC, Su WPD, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol.1996;34:395-409 2.Halilbasic E. Bile Acid Transporters and Regulatory Nuclear Receptors in the Liver and beyond. J Hepatol 2013: 58.1: 155-68. 3.Zollner G et al. Nuclear Receptors as Drug Targets in Cholestasis and Drug-induced Hepatotoxicity. Pharm & Ther 126.3 2010: 228-43. 4.Jonker, JW. et al. FXR and PXR: Potential Therapeutic Targets in Cholestasis. J. Steroid Biochem. Mol. Biol. 130.3-5 (2012): 147-58. 5.Albermann, N. et al. Expression of the Drug Transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in Peripheral Blood Mononuclear Cells and Their Relationship with the Expression in Intestine and Liver. Biochem. Pharmacol. 70.6 (2005): 949-58. 6.Klaassen CD. "Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation." Rev. of Pharmacological Reviews. American Society for Pharmacology and Experimental Therapeutics Mar. 2010: 1-96. 7.Wilkinson GR. Drug Metabolism and Variability among Patients in Drug Response. N Engl J Med.2005: 352: 2211-21. Pt 1. 10 months after cessation of PPI and MVI, dose reduction Neurontin, Probenacid. Addition of Danazol due to hypercoag state. All but two patients were obese. 6 of the 13 patients were on more than four drugs. The most complex drug lists included drug combinations for pain control. Two patients were on early generation synthetic progestins. One patient developed vulvar ulceration one month after starting a nutraceutical program for weight loss. Two patients had documented hypercoaguable states. Three exhibited early graying. One had pediatric onset restless leg syndrome. Nuclear Receptor for Bile AcidsNuclear Receptor for Xenobiotics PXR CAR PPAR Both PXR FXR CAR FXR PXR