What are the differences and similarities in the metabolism of prednisone, mycophenolate (Cellcept), hydrocodone, tofacitinib (Xeljanz), and leflunomide (Arava)?

From the Guidelines

The metabolism of prednisone, mycophenolate, hydrocodone, Xeljanz (tofacitinib), and leflunomide differs significantly based on their chemical structures and pharmacokinetic properties, with prednisone being metabolized to its active form prednisolone, mycophenolate mofetil being hydrolyzed to mycophenolic acid, hydrocodone undergoing extensive hepatic metabolism, Xeljanz being metabolized through the CYP3A4 pathway, and leflunomide being converted to its active metabolite teriflunomide. The metabolic pathways of these drugs are as follows:

• Prednisone is primarily metabolized in the liver where it is converted to its active form, prednisolone, through first-pass metabolism by 11β-hydroxysteroid dehydrogenase 1.
• Mycophenolate mofetil is rapidly hydrolyzed to its active form, mycophenolic acid, by esterases in the blood, liver, and intestinal tissue, then undergoes glucuronidation in the liver before being excreted primarily in urine 1.
• Hydrocodone undergoes extensive hepatic metabolism via CYP2D6 to hydromorphone (its active metabolite) and via CYP3A4 to norhydrocodone, with genetic variations in CYP2D6 significantly affecting its efficacy.
• Xeljanz (tofacitinib) is metabolized primarily through the CYP3A4 pathway with approximately 70% of the drug eliminated hepatically and 30% renally, with minimal active metabolites.
• Leflunomide is quickly converted in the gut wall and liver to its active metabolite teriflunomide (A77 1726) through first-pass metabolism, and has an extremely long half-life (1-4 weeks) due to enterohepatic recirculation, often requiring cholestyramine washout when discontinuation is needed. Understanding these metabolic pathways is crucial when considering drug interactions, dosing in organ dysfunction, and genetic variations that might affect drug efficacy and toxicity. Some key points to consider when prescribing these medications include:
• Monitoring for potential drug interactions, such as the interaction between mycophenolate and azathioprine, which can cause increased inhibition of purine metabolism 1.
• Adjusting dosing in patients with organ dysfunction, such as renal impairment, which can affect the metabolism and excretion of these drugs.
• Considering genetic variations, such as those affecting CYP2D6, which can significantly impact the efficacy and toxicity of hydrocodone.

From the FDA Drug Label

Following oral administration, leflunomide is metabolized to an active metabolite A77 1726 (hereafter referred to as M1) which is responsible for essentially all of its activity in vivo. The specific site of leflunomide metabolism is unknown In vivo and in vitro studies suggest a role for both the GI wall and the liver in drug metabolism. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug

• Metabolism Comparison:
  • Leflunomide: Metabolized to active metabolite M1, site of metabolism unknown, involves GI wall and liver
  • Tofacitinib (Xeljanz): Metabolized primarily by CYP3A4, with 70% hepatic metabolism and 30% renal excretion
• No information is available in the provided drug labels to compare and contrast the metabolism of:
  • Prednisone
  • Mycophenolate
  • Hydrocodone
  • Leflunomide and Xeljanz with the other three drugs Therefore, no conclusion can be drawn regarding the metabolism of these drugs 2, 3

From the Research

Metabolism Comparison

• The metabolism of prednisone is determined by the position of substituents in the molecule, with one of three possible main pathways: hydrogenation in ring A and/or the 20-position, 6beta-hydroxylation, or defluorination in the 6alpha-position and 6beta-hydroxylation 4.
• Mycophenolate is metabolized in the liver, gastrointestinal tract, and kidney by uridine diphosphate gluconosyltransferases (UGTs) to form 7-O-MPA-glucuronide (MPAG), which is then excreted into the urine or bile 5.
• Hydrocodone is metabolized by cytochrome P450 enzymes (CYPs) and uridine-5'-diphosphoglucuronosyltransferases (UGTs), with glucuronidation being an important pathway for opioid-drug interactions 6.
• There is no information available on the metabolism of xeljanz and leflunamide in the provided studies.

Pharmacokinetics and Pharmacodynamics

• Mycophenolate mofetil and enteric-coated mycophenolate sodium exhibit linear pharmacokinetics, with a mean elimination half-life of MPA ranging from 9 to 17 hours 5.
• The pharmacodynamics of mycophenolate are characterized by its potent, selective, and reversible inhibition of inosine monophosphate dehydrogenase (IMPDH), leading to eventual arrest of T- and B-lymphocyte proliferation 5.
• Hydrocodone, oxycodone, and morphine have narrow therapeutic indexes and are extensively used, making them prone to severe toxicity and drug-drug interactions 6.

Drug-Drug Interactions

• Mycophenolate therapy can be affected by co-medications, such as ciclosporin, which inhibits biliary excretion of MPAG, reducing enterohepatic recirculation of MPA 5.
• High dosages of corticosteroids may induce expression of UGT, reducing exposure to MPA 5.
• Opioids such as hydrocodone, oxycodone, and morphine can interact with other drugs through pharmacokinetic and pharmacodynamic mechanisms, including inhibition or induction of CYPs and UGTs 6.