Clearance

• Introduction

  • Clearance is especially important for insuring appropriate long-term drug dosing allowing for correct steady-state drug concentrations

• Clearance of a given drug is usually constant over the therapeutic concentration range because

  1. Drug elimination systems are not saturated; therefore, the absolute rate of elimination is a linear function of the drug's plasma concentration.

  2. Drug elimination is therefore usually a first-order kinetic process in which a constant fraction of the drug is eliminated per unit time.

  3. Some drugs (e.g., ethanol) exhibit zero order kinetics in which a constant amount of drug is eliminated per unit time. (Clearance is variable)

• Clearance: the drug's rate of elimination (by all routes) normalized to the concentration of drug C in some biological fluid.

  • CL = Rate of elimination / C

  • CL = Vd x k_el where V_d = volume of distribution and k_el is the elimination rate constant

  • CL = Vd x (0.693/t_1/2) where 0.693 = ln2 and t_1/2 is the drug elimination half-life

• Clearance

  • Volume per unit time (volume of fluid i.e. blood or plasma that would be completely freed of drug to account for the elimination)

  • May be defined as:

    • Blood clearance, CL_b

    • Plasma clearance, CL_p

    • Concentration of unbound or free drug, depending on the concentration measured (C_b, C_p or C_u)

• Clearance is additive: a function of elimination by all participating organs such as liver or kidney.

  • CL systemic = CL_renal + CL_hepatic + CL_other

    • "Other" sites may include the lungs and other sites of drug metabolism (muscle, blood)

    • The two most important sites for drug elimination: kidneys and liver

  • Renal clearance: clearance of unchanged drug and metabolites

    • Kidneys: most important organs for unchanged drug/drug metabolites elimination

    • Water-soluble compounds exhibit more efficient renal excretion compared to lipid soluble compounds (emphasizing the importance of metabolic conversion of lipid-soluble drugs to water-soluble metabolites)

    • Renal drug clearance is correlated with exogenous creatinine clearance or serum creatinine concentration

    • Factors in renal excretion:

      1. Glomerular filtration-- important considerations:

         • Fraction of free drug (compared to protein-bound drug)--when a drug is bound to protein it is not filtered

         • Glomerular filtration rate

      2. Tubular secretion (active process)-- important considerations:

         • Drug/metabolite selectivity

      3. Passive tubular reabsorption-- important considerations:

         • Enhanced lipid solubility favors reabsorption {lipid-soluble agents more readily cross renal tubular epithelial cell membrane thus entering pericapillary fluid}

         • Example: thiopental (highly lipid-soluble): completely reabsorbed -- minimal unchanged drug excreted in urine

         • Renal tubular reabsorption rate influenced by:

           • pH

           • Rate of renal tubular urine flow

           • Weak acid or weak base drug/drug metabolite pKa compared to urinary pH

  • Hepatic clearance: drug elimination following metabolic transformation of the parent drug to metabolites

    • Since elimination is not "saturable", elimination is typically first order and directly proportional to drug concentration:

• Other factors affecting renal clearance

  • Renal disease

  • Rates of filtration depend on:

    1. Volume filtered in the glomerulus

    2. Unbound drug concentration in plasma (plasma protein-bound drug is not filtered)

  • drug secretion rates:

    1. Extent of drug-plasma protein binding

    2. Carrier saturation

    3. Drug transfer rates across tubular membranes

    4. Rate of drug delivery to secretory sites

  • Changes in plasma protein concentration

  • Blood flow

  • Number of functional nephrons

• Factors affecting hepatic clearance

  •  Drug delivery to hepatic elimination sites may be rate-limiting for certain drugs:

    •  Also called flow dependent elimination: in this case most of the drug in the blood is eliminated on the first pass of the drug through the organ

    •  These drugs are termed "high-extraction"

  • Extent of plasma protein-bound drug

  • Blood flow (affects clearance on drugs with high extraction ratios).

Drugs that have Clearances greater than 6 ml/min./kg

Chlorpromazine: (antipsychotic) Diltiazem: (Ca2+ channel blocker) Imipramine: (tricyclic antidepressant) Lidocaine: (antiarrhythmic) Morphine: (opioid analgesic) Propoxyphene: (opioid analgesic) Propranolol: (beta adrenergic receptor blocker)

Verapamil: (Ca2+ channel blocker) Meperidine: (opioid analgesic) Desipramine: (tricyclic antidepressant) Amitriptyline: (tricyclic antidepressant) Isoniazid: (anti-tuberculosis)

• Changes in the intrinsic clearance (i.e. enzyme induction, hepatic disease: affects clearance of drugs with low extraction ratios): Examples include:

  • Social factors: 

    • Tobacco smoke induces some Cytochrome P450 (a.k.a. CYP) hepatic microsomal drug metabolizing enzyme isoforms (CYP1A1, CYP1A2, and possibly CYP2E1)

    • Chronic ethanol use induces CYP2E1

  • Dietary considerations:

    • Grapefruit juice contains chemicals that are potent inhibitors of CYP3A4 localized in the intestinal wall mucosa

    • Cruciferous vegetables such as brussels sprouts, cabbage, cauliflower and hydrocarbons present in charcoal-broiled meats can induce CYP1A2.

    • Calcium present in dairy products can chelate drugs including commonly used tetracyclines  and fluoroquinone antibiotics.

  • Age: Neonates have reduced hepatic metabolism and renal excretion due to relative organ immaturity.  On the other hand, elderly patients exhibit differences in absorption, hepatic metabolism, renal clearance and volume of distribution.

  • Genetic Factors:

    • Genetic polymorphism affecting CYP2D6, CYP2C19, CYP2A6, CYP2C9 (these abbreviations refer to different cytochrome P450 enzyme forms), and N-acetyltransferase result in significant inter-individual differences in drug-metabolizing abilities.

      •  The drug of course must be a substrate for one of the above cytochrome P450 isoforms.

    • Certain genetic polymorphisms are associated with ethic groups. 

      • For instance, 5%-10% of Caucasians are  poor metabolizers of CYP2D6 substrates. 

      • By contrast, the frequency in Asian populations is about 1%-2%. 

      • On the other hand, the incidence of poor metabolizers of CYP2C19 drugs is about 20% in Asian populations, but only about 4% in Caucasian populations.

    • Definition: genetic polymorphism:  "Genetic polymorphism is a type of variation in which individuals was sharply distinct qualities co-exist as normal members of the population" Ford, 1940.

• Capacity-limited elimination:

  • Drug examples includ ethanol and aspirin.

  • Capacity-limited elimination is both:

    1. Saturable, dose-or concentration-dependent

    2. Nonlinear

  • If blood flow to the organ does not limit elimination, the relationship between the elimination rate and drug concentration,C, is:

    • Rate of elimination = V_max · C / (K_m + C)

  References

  Holford, N. H.G. and Benet, L.Z. Pharmacokinetics and Pharmacodynamics: Dose Selection and the Time Course of Drug Action, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 34-49. Benet, Leslie Z, Kroetz, Deanna L. and Sheiner, Lewis B The Dynamics of Drug Absorption, Distribution and Elimination. In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp. 3-27 Stoelting, R.K., "Pharmacokinetics and Pharmacodynamics of Injected and Inhaled Drugs", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 1-17.