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What occurs when a drug displays nonlinear pharmacokinetics due to saturation of a metabolic pathway?
What occurs when a drug displays nonlinear pharmacokinetics due to saturation of a metabolic pathway?
What is a consequence of altering the administration schedule of drugs with nonlinear pharmacokinetics?
What is a consequence of altering the administration schedule of drugs with nonlinear pharmacokinetics?
How does doubling the 5-FU dose from 7.5 mg/kg to 15 mg/kg affect the mean AUC?
How does doubling the 5-FU dose from 7.5 mg/kg to 15 mg/kg affect the mean AUC?
In the context of nonlinear pharmacokinetics, what is the effect of a shorter infusion duration on AUC?
In the context of nonlinear pharmacokinetics, what is the effect of a shorter infusion duration on AUC?
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What happens when there is saturable absorption of a drug from the gastrointestinal tract?
What happens when there is saturable absorption of a drug from the gastrointestinal tract?
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Cisplatin exhibits nonlinear pharmacokinetics mainly due to saturation in which process?
Cisplatin exhibits nonlinear pharmacokinetics mainly due to saturation in which process?
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What observation was made regarding free plasma platinum in relation to infusion duration?
What observation was made regarding free plasma platinum in relation to infusion duration?
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Which of the following drugs exhibits saturable absorption due to active transport processes?
Which of the following drugs exhibits saturable absorption due to active transport processes?
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Which mechanism is primarily responsible for the active secretion of organic acids in the proximal tubules?
Which mechanism is primarily responsible for the active secretion of organic acids in the proximal tubules?
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What is a common feature of drugs that undergo active secretion in the renal system?
What is a common feature of drugs that undergo active secretion in the renal system?
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Which class of drugs would primarily use organic cation transport mechanisms for renal elimination?
Which class of drugs would primarily use organic cation transport mechanisms for renal elimination?
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How does the pH of urine affect the reabsorption of acidic drugs?
How does the pH of urine affect the reabsorption of acidic drugs?
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What is likely to happen if two drugs compete for the same renal secretion pathway?
What is likely to happen if two drugs compete for the same renal secretion pathway?
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Which drug is primarily cleared by active tubular secretion through organic anion transport systems?
Which drug is primarily cleared by active tubular secretion through organic anion transport systems?
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What is the expected renal clearance rate for drugs that undergo both glomerular filtration and active secretion?
What is the expected renal clearance rate for drugs that undergo both glomerular filtration and active secretion?
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Which of the following drugs is unlikely to be effectively filtered through the glomerulus due to its molecular size?
Which of the following drugs is unlikely to be effectively filtered through the glomerulus due to its molecular size?
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What primarily affects the extent of reabsorption for acidic and basic drugs with specific pKa values?
What primarily affects the extent of reabsorption for acidic and basic drugs with specific pKa values?
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How does the urine flow rate affect the reabsorption of weak acidic and weak basic drugs?
How does the urine flow rate affect the reabsorption of weak acidic and weak basic drugs?
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Which group of drugs has a bile to plasma concentration ratio less than 1?
Which group of drugs has a bile to plasma concentration ratio less than 1?
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What is the primary mechanism of biliary drug excretion compared to renal secretion?
What is the primary mechanism of biliary drug excretion compared to renal secretion?
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What type of drugs will have higher biliary clearance when their biliary concentration is greater than plasma concentration?
What type of drugs will have higher biliary clearance when their biliary concentration is greater than plasma concentration?
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Which of the following statements is true about forced diuresis in clinical practice?
Which of the following statements is true about forced diuresis in clinical practice?
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Which factor affects the renal clearance through influencing active secretion mechanisms?
Which factor affects the renal clearance through influencing active secretion mechanisms?
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What is a key factor that determines unchanged excretion of drugs in bile?
What is a key factor that determines unchanged excretion of drugs in bile?
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How does urine pH influence drug reabsorption in the renal tubules?
How does urine pH influence drug reabsorption in the renal tubules?
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Which of the following drug characteristics would most likely lead to inefficient biliary clearance?
Which of the following drug characteristics would most likely lead to inefficient biliary clearance?
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What is the primary consequence of competition in drug secretion within the kidneys?
What is the primary consequence of competition in drug secretion within the kidneys?
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What is the impact of sex on drug clearance levels?
What is the impact of sex on drug clearance levels?
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How does renal blood flow significantly influence drug clearance?
How does renal blood flow significantly influence drug clearance?
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Which characteristic of a drug would likely lead to a higher renal clearance rate?
Which characteristic of a drug would likely lead to a higher renal clearance rate?
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What does the elimination half-life of a drug indicate?
What does the elimination half-life of a drug indicate?
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Why is clearance considered the most critical parameter for determining maintenance dosing of medications?
Why is clearance considered the most critical parameter for determining maintenance dosing of medications?
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Study Notes
Nonlinear Pharmacokinetic Models
- Nonlinear pharmacokinetic models describe drug behavior where some aspect is saturable, meaning it can be overwhelmed with an increase in drug dose.
- Alterations in the administration schedule of drugs with nonlinear kinetics can significantly impact the area under the curve (AUC) and potentially change clinical effects.
- Saturation of a major metabolic pathway is a common cause of nonlinear pharmacokinetic behavior.
- This saturation leads to decreased clearance at higher doses and greater than proportional increases in the AUC.
- If the infusion duration is shortened, resulting in higher peak plasma concentrations, the AUC will also increase due to the slower clearance.
Examples of Nonlinear Pharmacokinetics
- 5-Fluorouracil (5-FU) exhibits nonlinear pharmacokinetics due to saturation of its conversion to dihydrofluorouracil by the enzyme dihydropyrimidine dehydrogenase.
- Doubling the 5-FU dose (from 7.5 mg/kg to 15 mg/kg) resulted in a 135% increase in the mean AUC.
- Paclitaxel also displays nonlinear pharmacokinetics.
- Shorter infusion schedules (3 hours vs. 24 hours) lead to higher AUC for a fixed dose of paclitaxel but do not result in increased toxicity.
Saturable Absorption
- Saturable absorption occurs when a drug's absorption from the gastrointestinal tract (or renal tubular reabsorption) is limited.
- In this case, an increase in dose results in a less than proportional increase in the AUC.
- Active transport processes that mediate the absorption of drugs resembling natural compounds often exhibit saturable kinetics.
- Folate analogs (Methotrexate, Leucovorin) and amino acid analogs (Melphalan) are examples of drugs with saturable absorption.
- Cisplatin demonstrates nonlinear pharmacokinetics due to saturation of its renal tubular reabsorption.
- Continuous 24-hour infusion of cisplatin resulted in a 42% increase in free plasma platinum compared to a 20-minute infusion.
- Prolonged infusion was also associated with a greater than threefold increase in the free platinum half-life.
Drug Clearance
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Factors affecting drug clearance:
- Drug properties: Molecular size, pKa, lipid solubility.
- Plasma concentration: Affects glomerular filtration, passive tubular reabsorption, and active secretion.
- Plasma protein binding: Only free drugs are excreted in urine.
- Renal blood flow: Affects glomerular filtration and active secretion.
- Sex: Females have lower clearance than males.
- Age: Newborns and elderly have lower clearance than adults.
- Drug interactions: Can alter active secretion, urine pH, and renal blood flow.
- Renal disease: Significantly impacts clearance.
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Importance of clearance:
- Determines the maintenance dose of a drug.
- Dosing rate = Rate of elimination = Clearance x Target plasma concentration
Elimination Half-Life (t1/2)
- Definition: Time it takes for the drug concentration in the body to be reduced by half.
- Misconception: Not equivalent to clearance.
- Steady-state vs. terminal half-life: Can differ significantly in some drugs.
- Effective half-life: In radionuclides, includes both physical and biological half-lives.
Drug Elimination
- Process: Drugs and their metabolites are permanently transferred from the body to the external environment.
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Routes:
- Renal: Via the kidneys.
- Nonrenal: Via the liver, intestine, lungs, skin, salivary glands, lacrimal glands, mammary glands, and semen.
Renal Drug Elimination
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Drug Properties: For renal elimination, a drug should be:
- Water soluble
- Non-volatile
- Small molecular size (generally <500 Da)
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Glomerular Filtration:
- Major route of drug excretion.
- Depends on renal blood flow and protein binding status.
- Macromolecular drugs cannot be filtered.
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Active Tubular Secretion:
- Most effective method of renal drug elimination.
- Carrier-mediated process requiring energy.
- Two systems:
- Organic anion transport: Penicillin, salicylates, furosemide, indomethacin, probenecid, and glucuronide conjugates.
- Organic cation transport: Morphine, mecamylamine, hexamethonium, amiloride, triamterene, quinine, and endogenous amines.
- Drugs with active secretion have clearance > 500 ml/min.
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Passive Tubular Reabsorption:
- Reversed transport of drugs back into the bloodstream.
- Dependent on urinary pH and drug pKa.
- Acidic drugs (pKa 3.0-8.0): Reabsorption influenced by urine pH.
- Basic drugs (pKa 6.0-12.0): Reabsorption influenced by urine pH.
- Reabsorption is inversely proportional to urine flow rate.
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Forced Diuresis: Used in poisoning to increase urine flow and decrease passive reabsorption.
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Urine acidification/alkalinization: Alters drug ionization in the tubular lumen, affecting reabsorption.
Nonrenal Drug Elimination
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Hepatic Drug Elimination (Biliary Excretion):
- Similar to active secretion, as bile secretion is capacity-limited.
- Biliary clearance: Bile flow x bile drug concentration / plasma drug concentration.
- Higher biliary concentration than plasma leads to higher biliary clearance.
- Compounds excreted in bile:
- Group A: Bile to plasma ratio ~1 (e.g., glucose, sodium, potassium).
- Group B: Bile to plasma ratio > 1 (e.g., bile salts, bilirubin, creatinine).
- Group C: Bile to plasma ratio < 1 (e.g., most drugs).
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Factors affecting biliary excretion:
- Drug polarity: Highly polar drugs are excreted unchanged in bile.
- Route of administration: Oral administration has more biliary excretion than parenteral administration.
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Description
Test your knowledge on nonlinear pharmacokinetic models and their implications in drug administration. Learn about drug behavior related to saturation and how it affects the area under the curve (AUC). This quiz will explore specific examples like 5-Fluorouracil and its metabolic pathways.
