Liver — Hepatic Clearance

Clearance (Cl)

Defined as the volume of plasma from which drug is completely removed per unit time (units – mL/min)

• Drug can be cleared from plasma via two routes:
  • “Elimination” from the body – Drug excreted unchanged (via renal or biliary routes) and/or metabolised (by liver or other organ)
    • Non-compartmental model: Cl = Dose / AUC
    • Compartmental model:  Cl=Vd x Kel = Vd x (ln2/t1/2)
  • “Intercompartmental clearance” (* occurs only in multi-compartment model *) – Drug distributes from the central to peripheral compartment(s) → determined by the rate constant for intercompartmental transfer (k12, k21; k13, k31; Etc.)
• Significance of clearance:
  • Determines maintenance dose rate needed to achieve a plasma [drug] at steady state
• “Maintenance dose rate” = Cl x desired [ ]PLASMA

Hepatic Extraction Ratio

Hepatic extraction ration (HER) – Fraction of drug that is irreversibly removed during 1st pass of blood through the liver → determined by intrinsic clearance (enzyme activity) and (ii) unbound % of drug

where
Q^_H = Hepatic Blood Flow
ER_Hep = Hepatic Extraction Ratio
F_U = fraction of drug unbound in plasma
Cl_Int = hepatic enzymatic capacity

Hepatic clearance

“Hepatic clearance” → determined by Hepatic Blood Flow and Hepatic Extraction Ratio

• Hepatic blood flow (HBF) – Rate at which drug is delivered to the liver
• Hepatic extraction ration (HER) – Fraction of drug that is irreversibly removed during 1st pass of blood through the liver → determined by intrinsic clearance (enzyme activity) and (ii) unbound % of drug

Hepatic clearance = HBF x HER = HBF x [(% unbound) x (intrinsic clearance)]

Important to note:

• Drugs with HER > 0.7 (↑ enzyme activity or “flow-limited”), such as GTN:
  • Hepatic drug clearance is dependent on HBF (“perfusion-dependent elimination”)
    → ↑ HBF will lead to ↑ hepatic drug clearance
  • Changes in HER (intrinsic enzyme activity or unbound %) have minimal effect on hepatic drug clearance as heaps of drug is already removed at a given time
    – i.e. Hepatic clearance ≈ HBF

• Drugs with HER < 0.3 (↓ enzyme activity or “capacity-limited”), such as diazepam:
  • Hepatic drug clearance is dependent on protein binding and intrinsic enzyme activity (“capacity-dependent clearance”)
    → ↑ enzyme activity and/or ↓ protein binding will ↑ hepatic drug clearance
  • Changes in HBF will have minimal effect on hepatic drug clearance as only a small % of drug is ever removed at a given time
    – i.e. Hepatic clearance ≈ HER = (unbound %) x (intrinsic clearance)

Other roles of liver in drug pharmacokinetics

Absorption (First pass metabolism):

• Drugs absorbed from GIT (except buccal and rectal mucosal) enter portal venous blood and pass through liver before entering systemic circulation
• They are metabolised by enzymes within the (i) liver (main) and (ii) gut wall (minor)
• FPM is a main reason why plasma [ ] after an oral dose is less cf. similar IV dose → as a result, it is a key determinant of oral bioavailability
• Significance – Drugs with ↓ FPM are either well-absorbed, stable in GIT, and/or have minimal hepatic metabolism → thus, have ↑ oral bioavailability (and ↑ plasma [ ]). The opposite is true for drugs with ↑ FPM

where,
F_B = Bioavailable fraction
F_A = Fraction absorbed
F_G = Fraction remaining after gut mucosal metabolism
F_H = Fraction remaining after hepatic metabolism

Metabolism:

Metabolism → process of chemically altering a drug within the body
Mainly occurs in liver (by hepatic microsomal enzymes), and few other sites

Effects of metabolism:

• ↓ drug activity (main effect): converts a “pharmacologically active” form of drug (Ie. non-polar and lipid soluble) into a “pharmacologically inactive” form (Ie. more polar and water-soluble) that can be excreted from the body (esp in bile or urine)
• ↑ drug activity: “Prodrug” → active moiety (Eg. enalapril → enalaprilat; parecoxib → valdecoxib)
• Produce metabolites with equal activity to parent compound (Eg. diazepam, propranolol)

Phases of metabolism:

• Phase I (functionalisation or non-synthetic):
  • Alter drug reactivity for phase II reaction and to ↑ drug polarity/water-solubility
  • Oxidation Including Hydroxylation (Eg. propofol), desulphation (Eg. STP), dealkylation (Eg. vecuronium), dehalogenation (Eg. volatiles), deamination, Reduction, Hydrolysis
• Phase II (conjugation or synthetic)
  • ↑ water solubility of drug or its metabolite by conjugating it to a polar endogenous moiety (Eg. sulphate, glucuronyl, methyl, Etc.) → permits excretion in urine or bile
  • Glucuronidation via glucuronosyltransferase (Eg. morphine, propofol)
    • UDP-glucuronic acid is conjugated to the drug → conjugate is inactive and water-soluble → excreted in urine/bile
    • Conjugated undergoes “enterohepatic recirculation” if eliminated in bile → intestinal bacterial glucuronidases hydrolyses glucuronide → liberates free drug which is reabsorbed back into circulation → results in prolonged drug action
  • Other reactions: Sulphation, Acetylation, Methylation, Glutathione via glutathione-S-transferase (Eg. EtOH)
  • Note – All these reactions involve non-microsomal enzymes, EXCEPT for glucuronidation (requires hepatic CYP450 microsomal enzymes)

Source: Bianca’s notes

JC 2019

Answer by JC