ZIDOVUDINE

• Action to be taken: No action needed
• Rationale: Zidovudine is a prodrug that is phosporylated to active metabolite zidovudine triphosphate. However the major pathway of metabolism if glucoronidation that leads to formation of zidovudine glucoronide which is then renally excreted. 

LAMIVUDINE

• Action to be taken: No action needed
• Rationale: Lamivudine is a prodrug phosphorylated to active metabolite lamivudine triphsophate. Metabolism is a minor route of elimination and only about 5% is metabolized to inactive trans -sulfoxide metabolite. About 70% of limavudine is eliminated unchanged in urine.

ABACAVIR

• Action to be taken: No action needed
• Rationale: Abacavir is not significantly metabolized by CYP450 enzymes. The two major pathways of metabolism are by alcohol dehydrogenase or glucoronyl transferase which result in inactive metabolites. Additionally in vitro studies show that abacavir does not inhibit CYP3A4, CYP2D6 or CYP2C9.

DIDANOSINE

• Action to be taken: No action needed
• Rationale:Didanosine is rapidly phosphorylated to active metabolite dideoxyadenosine triphosphate which is then hepatically metabolized to uric acid, xanthine, and hypoxanthine. Based on data from animal studies its believed that the majority of the drug 50 -80% is eliminated unchanged in urine.

STAVUDINE

• Action to be taken: No action needed
• Rationale: Stavudine is unlikely to interact with drugs metabolized by CYP450 enzymes as it does not inhibit 
  CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.Stavudine is an analog of thymidine thats phosphorylated by cellular kinases to active metabolite stavudine triphosphate. It is quickly absorbed and eliminated.  Approximately 40% of stavudine is excreted unchanged in the urine by both glomerular filtration and net renal tubular secretion in HIV infected patients.  Its unclear what happens with the remainder, however in vitro and in vivo data suggest that stavudine is metabolized. Some of the degradation products are believed to be glucoronide conjugates, oxidized stavudine and N-Acetylcysteine conjugates

TENOFOVIR

• Action to be taken: Caution, possible interaction
• Rationale:  In vitro studies have shown that tenofovir does not inhibit in vitro drug metabolism mediated by any of the following CYP450 enzymes CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a statistically significant reduction (6%) in metabolism of CYP1A substrate was observed. Tenofoivr has a low protein binding  of less than 1 %.  It is majorly eliminated unchanged in urine by glomerular filtration and active tubular secretion . Based on the results of in vitro experiments and the elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low. 

EMITRACIBINE

• Action to be taken: No action needed
• Rationale:  In vitro studies have shown that emtricitabine does not inhibit in vitro drug metabolism mediated by any of the following CYP450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.  Emitracibine is an analog of cytidine and it is phosphorylated to an active metabolite emitacibine 5-triphosphate. It is mainly eliminated through renal excretion, where 86% is recovered unchanged in urine.  The renal clearance of emtricitabine is greater than the estimated creatinine clearance, suggesting elimination by both glomerular filtration and active tubular secretion. Based on the results of in vitro experiments and the known elimination pathways of emtricitabine, the potential for CYP mediated interactions involving emtricitabine with other medicinal products is low. 
  
   
  

References

1. Gareth J. Veal, David J. Back, Metabolism of zidovudine, General Pharmacology: The Vascular System, Volume 26, Issue 7, 1995, Pages 1469-1475, ISSN 0306-3623, http://dx.doi.org/10.1016/0306-3623(95)00047-X.
   
2. Retrovir (zidovudine) package insert, GlaxoSmithKline, Research Triangle Park, NC. 2008
3. Epivir(lamivudine) package insert, GlaxoSmithKline, Research Triangle Park, NC. 2002
4. Mark A. Johnson, Katy H.P Moore, Pharmacokinetics of lamivudine, Clinical Pharmacokinetics, Volume 36, Issue 1, 1999, Pages 41 -66.
5. Yuen GJ, Welles S, Pakes SF, A review of the pharmacokinetics of abacavir. Clinical Pharmacokinetics, Volume 47, Issue 6, 2008, Pages 351 -351.
6. Ziagen (abacavir) package insert, GlaxoSmithKline, Research Triangle Park, NC. 2015
7. S Kaul, W C Shyu, U A Shukla, K A Dandekar and R H Barbhaiya, Absorption, disposition, and metabolism of [14C]didanosine in the beagle dog.Drug Metabolism and Disposition May 1, 1993,  21 (3) 447-453
8. ​Videx (didanosine) package insert, Bristol-Myers Squibb Company Princeton, NJ 2015
9. Zerit (stavudine) package insert, Bristol-Myers Squibb Company Princeton, NJ 2012
10. Rana K Z,Dudley M, Clinical pharmacokinetics of stavudine. Clinical Pharmacokinetics,Volume 33, Issue 4, 1997 Pages 276–284
11. Kearny B P, Flaherty J F, Shah J, Tenofovir Disoproxil Fumarate.Clinical Pharmacokinetics,Volume 43, Issue 9, 2004 Pages 295-612
12. Viread(tenofovir) package insert, Gilead Sciences, Inc. Foster City, CA. 2017
13. Valade E, Tréluyer J-M, Bouazza N, et al. Population Pharmacokinetics of Emtricitabine in HIV-1-Infected Adult Patients. Antimicrobial Agents and Chemotherapy. 2014;58(4):2256-2261. doi:10.1128/AAC.02058-13.
14. Emtriva(emitracibine) package insert, Gilead Sciences, Inc. Foster City, CA. 2012