Drug transport and metabolism pathways in Chronic Renal Dysfunction or Failure (CRDF)

The potential drug, Tecarfarin, may offer advantages to patients with chronic renal disease who also require anti-coagulants. The drug candidate’s breakdown and metabolism mechanism is different from competitor medications and may result in fewer drug interactions and less concern for its impact on renal function.

Background

The accumulation of breakdown products that accumulate due to renal dysfunction, referred to as uremic toxins, have been implicated in a number of problems in uremic patients, including bleeding tendencies from platelet dysfunction, hypertension, cardiac failure, neuropathy, defective protein binding of drugs, irregularities in thyroid function, and inhibition of drug metabolism in the liver.

Patients with chronic renal dysfunction or failure (CRDF) show impaired drug elimination mainly because of impaired glomerular filtration rate that has a direct effect on the elimination of drugs normally excreted by the kidneys. However, this is not the whole story, as there are indirect factors of CRDF that significantly alter the transport and metabolism of drugs eliminated by the liver.

Indeed, several studies have shown that the metabolic clearance of various substrates is reduced in patients with CRDF. The severity of the inhibition of hepatic drug metabolism in CRDF varies from 17% to 85% depending on the metabolic pathway involved and depending on the severity of the disease, but drugs metabolized by hepatic cytochrome P450 (CYP450) are particularly vulnerable. Therefore, appropriate dosing of drugs in renal insufficiency is an important consideration to avoid an increased incidence of adverse effects and to ensure optimal patient outcomes.

This impaired drug elimination function is not restricted to end-stage renal disease (ESRD) patients. The situation is much wider than originally believed and affects CRDF patients, which are NYHA Class-III and above (i.e., moderately-reduced kidney function and above; glomerular filtration rate GFR<60). These patients commonly take several medications to treat their underlying condition, i.e., diabetes, hypertension, infection, etc., and a significant number of these medications are likely to be CYP450 inhibitors, which further compounds the difficulty of the situation.

Effect of CRDF on hepatic CYP450 functional expression

There are compelling data available to indicate that alterations in non-renal drug clearance occur in patients with CRDF. Non-renal clearance consists mainly of hepatic CYP450 metabolism. Several studies have demonstrated modifications in the functional expression of CYP450 enzymes in experimental models of uremia, and various uremic by-products (e.g., “uremic toxins”) have been implicated, including urea, parathyroid hormone, and indoxyl sulfate. In humans, decreased CYP2C9 and CYP3A4 activities have been reported in uremic patients, which could have significant clinical implications because numerous CYP2C9 and CYP3A4 substrates are frequently prescribed to these patients.

Reversal of the uremic state following kidney transplantation leads to a sustained improvement in hepatic metabolism. Hemodialysis also improves uremia, but only temporarily. Once on chronic hemodialysis, the metabolic deficit persists, as measured by the erythromycin breath test, an indicator of hepatic CYP3A4 activity.

The decrease in CYP450 activity and expression mediated by uremic serum appears to be rather specific to CYP450 isoforms and not to other hepatic proteins. The decrease in CYP450 activity also appears to correlate with the severity of the disease, which suggests that as CRDF worsens, patients are at an increased risk of drug toxicity.

Mechanism studies point to a decrease in CYP450 gene expression responsible for the decreased metabolic activity, and the mediators responsible for decreased CYP450 activity appear to have a mass of between 10 and 15KDa. This and various other clues point to parathyroid hormone (PTH) and cytokines as the mediators responsible for decreased CYP450 metabolism in CRDF patients.

Effect of CRDF on drug transport and the inter-relationship with CYP450 metabolism

In CRDF patients, the decreased elimination profile of drugs that are not renally excreted is consistent with the effect of uremic toxins on either intestinal or hepatic cell transporters as well as with their effect on metabolizing enzymes, or both.

It is now clear that uremia associated with advanced kidney disease (i.e., Class-IV and V), can impact both the metabolism and the transport of non-renally cleared drugs, and has differential effects on these pathways in the liver and in the GI tract. P-gp for example appears to be down-regulated in the GI tract, resulting in increased intestinal absorption of P-gp substrates, but is up-regulated in hepatocytes, resulting in increased biliary elimination.

Another efflux transporter, MRP2, is down-regulated in the GI tract but unchanged in the liver. The complex relationship between metabolic enzymes and transporters, when added to the differential effects in the liver and GI tract, leads to a multitude of possible scenarios, which is another way to say that the result is unpredictable.

For instance, P-gp and MRP2 substrates may show enhanced intestinal absorption due to a decreased functional expression of these efflux transporters in the intestine, but a more rapid elimination due to their enhanced expression in the liver, resulting in more, less, or unchanged amount of drug in the body.

Similarly, down-regulation of CYP3A4 enzymes, which appear particularly sensitive to CRDF, could reduce intestinal first-pass metabolism and thereby lead to increased bioavailability. These changes probably explain why the bioavailability of several drugs like erythromycin, propranolol, and tacrolimus, is enhanced in kidney disease.

Key points:

1. In chronic renal dysfunction or failure, uremic toxins accumulate in the systemic circulation
2. The toxins modulate the expression and activity of metabolism enzymes such as Cytochrome – P450 dependent enzymes as well as transporter proteins such as, P-gp.
3. Drugs that are excreted via the kidney, metabolized by CYP450 enzymes and/or transported by P-gp will adversely affect the systemic bioavailability of itself and other drugs that have the same properties.
4. As a drug candidate, Tecarfarin seeks to avoid CYP450-dependancy and avoid renal elimination, making it an anti-coagulant with future potential for patients with renal insufficiency.