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Methotrexate (MTX; molecular weight 454) is a drug used in the treatment of certain neoplastic disorders, severe psoriasis and adult rheumatoid arthritis. It is a carboxylic acid with a pK, value of 4.4. Below are some important pharmacokinetic parameters for MTX: Parameter Volume of distribution, Va % Plasma protein bound Renal Clearance, CL Value 0.6 L/kg 50 % 2.0 mL/min/kg MTX is generally well absorbed after oral administration of low doses. Because urinary excretion is the major elimination pathway for MTX from the body, high MTX concentrations are reached in the tubular filtrate. Impaired renal function can cause MTX toxicity. After IV administration, 80% of the administered dose is excreted unchanged in the urine, 10% of the administered dose is excreted in the bile, presumably by biliary excretion and the remainder of the dose is metabolized. It is believed that some MTX undergoes enterohepatic recirculation. 1. What is the volume of distribution (in liters) of MTX in a patient weighing 70 kg? What does this number tell you about the fluids into which MTX distributes? 2. Renal excretion is the primary elimination pathway for MTX. The drug undergoes glomerular filtration, tubular secretion and reabsorption. What factors determine glomerular filtration?
3.a. What is the ionization state (mostly ionized or unionized) of MTX molecules at physiologic pH (7.4)? Calculate the ratio of unionized to ionized. b. Given the ionization state of MTX at pH 7.4, how can it be transported into and across tissue cells? 4a. Using the numbers in the table, calculate the Glomerular Filtration Rate (GFR) of MTX in an individual with normal kidney function. The average GFR for a healthy human is 120 mL/min b. Using the numbers in the table, calculate the renal clearance of MTX in a 70 kg human with normal kidney function. c. Compare the GFR of MTX to the renal clearance of MTX calculated in 4a and 4b. Based on this comparison, does secretion or reabsorption predominate in the urinary excretion of MTX?
5. MTX has poor intrinsic solubility and may precipitate in the urine, particularly at high doses. Precipitation can cause renal failure, will also delay further MTX elimination, and is a potentially life-threatening complication. To avoid precipitation of MTX in the urine, clinicians often hydrate patients aggressively, and administer sodium bicarbonate. a. Explain how aggressive hydration can reduce the chances of MTX precipitation in the urine. b. Explain how sodium bicarbonate can change the ionization state of MTX in the urine. c. Will changing the urine pH by sodium bicarbonate have any effect on the extent of glomerular filtration, tubular secretion, or tubular reabsorption of MTX? How might this change the renal clearance of MTX? 6. The renal clearance of MTX often decreases at high doses. Explain why this might occur. 7. Concurrent use of other weak organic acid drugs (such as nonsteroidal anti- inflammatory drugs) with MTX can result in the persistence of MTX in the body. Explain.
8. MTX is excreted to some extent in bile. What properties of MTX favor biliary excretion? Where will the drug excreted in bile end up?