Hepatic Clearance Lecture Notes PDF

HEPATIC CLEARANCE Dr.Nermine M Hamed Pharm D, Ph D HEPATIC CLEARANCE The decline from peak plasma concentration after drug administration results from drug elimination or removal by the body. The elimination of most drugs from the body involves the process of both metabolism (biotransformatio...

HEPATIC CLEARANCE Dr.Nermine M Hamed Pharm D, Ph D HEPATIC CLEARANCE The decline from peak plasma concentration after drug administration results from drug elimination or removal by the body. The elimination of most drugs from the body involves the process of both metabolism (biotransformation) and renal excretion. For many drugs, the principal site of metabolism is the liver. Whether a change in drug elimination is more likely to be affected by renal disease, hepatic disease, or a drug-drug interaction may be predicted by measuring the fraction of the drug that is eliminated by either metabolism or excretion. Drugs that are highly metabolized (such as phenytoin, theophylline, and lidocaine) often demonstrate large intersubject variability in elimination half-lives and are dependent on the intrinsic activity of the biotransformation enzymes, which may vary by genetic and environmental factors. Intersubject variability in elimination half-lives is less for drugs that are eliminated primarily by renal drug excretion. Renal drug excretion is highly dependent on the GFR and blood flow to the kidney. Since GFR is relatively constant among individuals with normal renal function, the elimination of drugs that are primarily excreted unchanged in the urine is also less variable 2  FIRST-ORDER ELIMINATION The rate constant of elimination (k) is the sum of the first-order rate constant for metabolism (km) and the first- order rate constant for excretion (ke): 𝑘 = 𝑘𝑒 + 𝑘𝑚 In practice, the excretion rate constant (ke) is easily evaluated for drugs that are primarily renally excreted. Nonrenal drug elimination is usually assumed to be due for the most part to hepatic metabolism. Therefore, the rate constant for metabolism km is difficult to measure directly and is usually obtained from the difference between k and ke. 𝑘𝑚 = 𝑘 − 𝑘𝑒 A drug may be biotransformed to several metabolites (metabolite A, metabolite B, metabolite C, …etc); thus, the metabolism rate constant km is the sum of the rate constants for the formation of each metabolite: 𝑘𝑚 = 𝑘𝑚𝐴 + 𝑘𝑚𝐵 + 𝑘𝑚𝐶 + ⋯ The relationship in this equation assumes that the process of metabolism is first order and that the substrate (drug) concentration is very low. Drug concentrations at therapeutic plasma levels for most drugs are much lower than the Michaelis-Menten constant KM, and do not saturate the enzymes involved in metabolism. Nonlinear Michaelis-Menten kinetics must be used when drug concentrations saturate metabolic enzymes. Because these rates of elimination at low drug concentration are considered first-order processes, the percentage of total drug metabolized may be obtained by the following expression: 𝑘𝑚 % 𝑑𝑟𝑢𝑔 𝑚𝑒𝑡𝑎𝑏𝑜𝑙𝑖𝑧𝑒𝑑 = ∗ 100 𝑘 3 Fraction Of Drug Excreted Unchanged (Fe) And Fraction Of Drug Metabolized (1-fe) For most drugs, the fraction of dose eliminated unchanged (fe) and the fraction of dose eliminated as metabolites can be determined. For example, consider a drug that has two major metabolites and is also eliminated by renal excretion. Assume that 100mg of the drug was given to a patient and the drug was completely absorbed (bioavailability factor F=1). A complete (cumulative) urine collection was obtained, and the quantities in parentheses in the following figure indicate the amounts of each metabolites and unchanged drug that were recovered. The overall elimination half-life t1/2 for this drug was 2 hours (k=0.347hr-1). 4  Metabolite A (10 mg) Drug Metabolite B (100 mg) (20 mg) Unchanged drug in urine (70 mg) 5  To determine the renal excretion rate constant, the following relationship is used: 𝑘𝑒 𝑡𝑜𝑡𝑎𝑙 𝑑𝑜𝑠𝑒 𝑒𝑥𝑐𝑟𝑒𝑡𝑒𝑑 𝑖𝑛 𝑢𝑟𝑖𝑛𝑒 𝐷𝑢∞ = = 𝑘 𝑡𝑜𝑡𝑎𝑙 𝑑𝑜𝑠𝑒 𝑎𝑏𝑠𝑜𝑟𝑏𝑒𝑑 𝐹𝐷0 Where 𝐷𝑢∞ is the total amount of unchanged drug recovered in the urine. In this example, ke is found by proper substitution in the previous equation: 70 𝑘𝑒 = 0.347 = 0.243 ℎ𝑟 −1 100 To find the percent of drug eliminated by renal excretion, the following approach may be used: 𝑘𝑒 0.243 𝑓𝑒 = = = 0.7 𝑘 0.347 Alternatively, because 70mg of unchanged drug was recovered from a total dose of 100mg, the percent of drug excretion may be obtained by 70 % 𝑑𝑟𝑢𝑔 𝑒𝑥𝑐𝑟𝑒𝑡𝑒𝑑 = ∗ 100 = 70% 100 Therefore, the percent of drug metabolized is 100%-70%, or 30%. For many drugs, the literature has approximate values for the fraction of the drug excreted unchanged (fe) in the urine. In this example, the value of ke may be estimated from the literature values for the elimination half-life of the drug and fe. Assuming that the elimination half-life of the drug is 2hrs and fe is 0.7, then ke is estimated by this equation 𝑘𝑒 = 𝑓𝑒 𝑘 k=o.693/2=0.347h-1 𝑘𝑒 = 0.7 ∗ 0.347 = 0.243ℎ −1 6 HEPATIC CLEARANCE The clearance concept may be applied to any organ and is used as a measure of drug elimination by the organ. Hepatic clearance may be defined as the volume of blood that perfuses the liver which is cleared of drug per unit of time. 𝐶𝑙 𝑇 = 𝐶𝑙𝑅 + 𝐶𝑙𝑁𝑅 Where 𝐶𝑙 𝑇 is total body clearance, Clnr is nonrenal clearance (often equated with hepatic clearance ClH), is also equal to total body clearance ClT minus renal clearance ClR assuming no other organ metabolism. 𝐶𝑙𝐻 = 𝐶𝑙 𝑇 − 𝐶𝑙𝑅 7 PROBLEM I The total body clearance for a drug is 15ml/min/kg. Renal clearance accounts for 10ml/min/kg. What is the hepatic clearance for the drug? PROBLEM II The total body clearance for a drug is 10ml/min/kg. The renal clearance is not known. From a urinary drug excretion study, 60% of the drug is recovered intact and 40% is recovered as metabolites. What is the hepatic clearance for the drug, assuming that metabolism occurs in the liver? 8 FIRST-PASS EFFECTS For some drugs, the route of administration affects the metabolic rate of the compound. For example, a drug given parenterally, transdermally, or by inhalation may distribute within the body prior to metabolism by the liver. In contrast, drugs given orally are normally absorbed in the duodenal segment of the small intestine and transported via the mesenteric vessels to the hepatic portal vein and then to the liver before entering the systemic circulation. Drugs that are highly metabolized by the liver or by the intestinal mucosal cells demonstrate poor systemic availability when given orally. This rapid metabolism of an orally administered drug before reaching the general circulation is termed first-pass effect or pre-systemic elimination. 9 EVIDENCE OF FIRST-PASS EFFECTS First-pass effects may be suspected when there is relatively low concentrations of parent (or intact) drug in the systemic circulation after oral compared to IV administration. In such a case, the AUC for a drug given orally also is less than the AUC for the same dose of the drug given intravenously. So the absolute bioavailability F may reveal evidence of drug being removed by the liver due to first-pass effects as follows: 𝐴𝑈𝐶𝑃𝑂. 𝐷𝐼𝑉 𝐹𝑎𝑏𝑠 = 𝐴𝑈𝐶𝐼𝑉. 𝐷𝑃𝑂 For drugs that undergo first-pass effects, AUCPO is smaller than AUCIV and F