Pharmacokinetics of Protein-Bound Drugs

Protein Bound Drugs

• Not eliminated by glomerular filtration, only the free drug is excreted through a linear process.

• Bound drugs are usually excreted by active secretion, which follows capacity-limited kinetics.

• The determination of clearance separates two components, resulting in a hybrid drug that has different elimination pathways.

  The clearance of a protein-bound drug is complex and cannot be easily predicted, as it involves both filtration and secretion.

• There is no simple way to overcome the problem of determining clearance for protein-bound drugs.

Drug Clearance

• Drug clearance is the intrinsic ability of the body or its organs (usually kidneys and liver) to remove a drug from the blood or plasma.
• Clearance is not an indicator of how much drug is being removed, but rather represents the theoretical volume of blood or plasma that is completely cleared of a drug in a given time period.

Factors Affecting Clearance

• Amount of drug removed depends on plasma concentration of drug and clearance.

Steady State

• Steady state is achieved when the rate of drug administration (RA) equals the rate of drug elimination (RE).

Mathematical Representation of Clearance

• Clearance (Cl) = rate of drug elimination divided by plasma drug concentration at that time point.
• Cl = excretion rate / plasma concentration (Equation 1)

Total Body Clearance

• Total body clearance is the sum total of all clearance pathways in the body, including clearance of drug through the kidney (renal clearance) and liver (hepatic clearance).
• Expressed per kilogram body weight.

Renal Clearance

• Renal clearance is the quantitative description of the renal excretion of drugs.
• Renal excretion is a major route of elimination for many drugs, especially water-soluble drugs with low molecular weight (< 300) or those that are slowly biotransformed by the liver.

Mechanisms of Renal Clearance

• Glomerular filtration: a unidirectional process, occurs for most small molecules, including undissociated and dissociated drugs.
• Active tubular secretion: an active process that requires energy, involves a carrier-mediated system, and may be saturated.
• Tubular reabsorption: may be active or passive, influenced by pH of the renal tubule and pKa of the drug.

Glomerular Filtration

• Glomerular filtration rate is measured by using a drug that is eliminated by filtration only, such as inulin or creatinine.
• Clearance of inulin will be equal to the glomerular filtration rate, which is approximately 125-130 ml/min.
• Glomerular filtration is directly related to the free or non-protein-bound drug concentration in the plasma.

Active Tubular Secretion

• Active tubular secretion is an energy-dependent process that requires a carrier system.
• Carrier-mediated system may be saturated, and drugs with similar structures may compete for the same carrier system.
• Active tubular secretion rate is dependent on renal plasma flow.

Tubular Reabsorption

• Tubular reabsorption can be active or passive.
• pH of the renal tubule and pKa of the drug influence the reabsorption of drugs.
• Undissociated species is more lipid-soluble and has greater membrane permeability, making it easier to reabsorb.

Henderson-Hasselbalch Equation

• pH = pKa + log [ionized] / [unionized]
• Used to calculate the percentage of ionized weak acid or weak base drug in a given pH environment.

Application of Henderson-Hasselbalch Equation

• The percentage of weak acid drug ionized in any pH environment can be calculated using the equation.
• Weak acids with pKa values of less than 2 are highly ionized at all urinary pH values and are only slightly affected by pH variations.
• Weak bases with pKa values of more than 8 are highly ionized at all urinary pH values and are only slightly affected by pH variations.### pH and Urinary Excretion of Weak Acids and Bases
• The Henderson-Hasselbalch relationship can be used to derive an equation for the concentration ratio of a weak acid or basic drug between urine and plasma.
• The urine:plasma ratios for weak acids and bases can be calculated using the following equations:
  • For weak acids: Urine/Plasma = (1+10^(pHurine-pKa)) / (1+10^(pHplasma-pKa))
  • For weak bases: Urine/Plasma = (1+10^(pKa-pHurine)) / (1+10^(pKa-pHplasma))
• The effect of urinary pH on reabsorption is greatest for weak bases with a pKa of 7.5-10.5.
• Alkalization of the urine increases the excretion of weak acids, while acidification of the urine increases the reabsorption of weak bases.

Renal Clearance

• Renal clearance (ClR) is the rate of elimination of a drug by the kidney.
• ClR can be calculated using the following equation: ClR = (Filtration rate + Secretion rate - Reabsorption rate) / C (plasma drug concentration)
• ClR can also be calculated using the following equation: ClR = (Total amount of drug excreted over some time interval) / (Plasma conc. measured at midpoint of time interval)

Maintenance Dose

• The maintenance dose is the dose that will produce a desired average plasma concentration at steady state.
• The maintenance dose can be calculated using the following equation: Maintenance dose = (Cl)(Css ave)(τ) / (S)(F)

Factors that Alter Clearance

• Factors that can alter clearance include:
  • Body weight and surface area
  • Cardiac output
  • Drug-drug interactions
  • Extraction ratio
  • Genetics
  • Hepatic function
  • Plasma protein binding
  • Renal function
• Clearance can be adjusted for a patient's body weight and surface area using the following equations:
  • Cl = (Literature Cl per m2) (Patient's BSA)
  • Cl = (Literature Cl per 70kg) (Patient's BSA / 1.73 m2)
  • Cl = (Literature Cl per kg) (Patient's weight in kg)

Renal and Hepatic Function

• The total clearance (ClT) is the sum of the renal clearance (Clr) and metabolic clearance (Clm).
• ClT = Clr + Clm
• In patients with renal or hepatic failure, the total clearance can be adjusted using the following equation: Cl adjusted = Clm + [(Clr) (Fraction of normal renal function remaining)]

Dosing Rate Adjustment Factor

• The dosing rate adjustment factor is used to adjust the maintenance dose for a patient with altered renal function.

• The dosing rate adjustment factor can be calculated using the following equation: Dosing rate adjustment factor = (Fraction eliminated metabolically) + [(Fraction eliminated renally) (Fraction of normal renal function remaining)]

• The dosing rate adjustment factor is used to adjust the maintenance dose for a patient with altered renal function.### Pharmacokinetics and Renal Clearance

• The learning outcome of this chapter is to understand the relation between Clearance (CL) and Volume of distribution (V).

• CL can be calculated when the rate constant (kn) is 101/day and V is 100 L.

Mechanisms of Clearance

• Renal clearance is an important mechanism, accounting for 50% of drug elimination.
• Metabolism accounts for 33% of drug elimination, with 17% of the drug being eliminated through other routes.

Dosing Rate Adjustment for Renal Impairment

• The dosing rate adjustment factor can be calculated using the formula: (Fraction Eliminated metabolically) + [(Fraction eliminated renally) × (Fraction of normal renal function remaining)].
• For a drug with 33% metabolic elimination, 50% renal elimination, and 60% remaining renal function, the dosing rate adjustment factor would be: 0.33 + (0.5 × 0.6) + 0.17 = 0.8.

Significance of Renal Function in Dosing

• Renal function affects drug clearance, and dosing adjustments are necessary in cases of renal impairment.
• Kidney function is critical in drug elimination, and dosing rates must be adjusted accordingly.