Elimination - Metabolism & Excretion PDF

# ELIMINATION - metabolism & excretion ## (i) Explain the elimination processes and concepts of clearance, extraction ratio, and intrinsic hepatic clearance ### **Metabolism** - Conversion of parent drug to metabolites (chemical species) - Parent drug (active) → Metabolite (inactive) - Dr...

# ELIMINATION - metabolism & excretion ## (i) Explain the elimination processes and concepts of clearance, extraction ratio, and intrinsic hepatic clearance ### **Metabolism** - Conversion of parent drug to metabolites (chemical species) - Parent drug (active) → Metabolite (inactive) - Drug passed out by urine MUST be soluble → More polar for excretion - **Phase I reactions:** Oxidation, Reduction, Hydrolysis - **Phase II reactions:** Conjugation with polar endogenous compounds - Major sites: Liver or intestinal mucosa - Metabolites can be pharmacologically active → Increases complexity → Parent + metabolites are active → Longer effect ### **Excretion** - Major sites of excretion of unchanged parent drug: - **Kidneys (glomerular filtration, tubular secretion)** (Most common) - **Biliary tract in liver** (High Molecular weight drugs, Conjugate metabolites) - **Lungs** for volatile agents (Anesthetics) - Renal and biliary excretion often involve drug transporters that can concentrate drug in urine and bile, respectively. ### **Clearance** - The volume of blood/plasma cleared of drug per unit time - **Clearance of a drug is the proportionality factor that predicts the rate of elimination in relation to the drug concentration** - *d A/dt* = *Rate of elimination* = *CL * *C* -*CL*= *Rate of Elimination* / *C* = *mg/min*/*mg/mL* = *mL/min* -*CL* may be defined with respect to blood (*CLb*), plasma (*Cl*), or unbound in water (*CLu*) depending on where and how the concentration is measured. - *Rate of elimination*= *CL* *x* *C* = *CLb* *x* *Cb* = *CLu* *x* *Cu* - By determining the *C/Co* ratio experimentally, one can convert *CL* to *CLb* and vice versa. ## → Elimination of drug from the body involves processes occurring in the kidney, lung, liver, and other organs - *Rate of elimination* = *Rate of hepatic elimination* + *Rate of renal elimination* + *Rate of elimination by other organs* - *CL total* = *CLh* + *CLr* + *CL other* - *CL total* = *CLrenal* + *CL non-renal* - Clearance of drug by one organ adds to the clearance of another (except pulmonary clearance since it doesn't receive the same *CA* as other organs due to its serial arrangement with the heart) - These separate organ clearances added together give the total systemic *CL* (*CLT*) - **By organ:** - *Hepatic clearance* (*CLh*) - *Renal clearance* (*CLr*) - *Pulmonary clearance* - **By process:** - *Metabolic clearance* (*CLm*) - *Excretory clearance* (*CL excretion*) - *Biliary clearance* (*CL biliary*) - **By site of measurement:** - *Hepatic metabolic plasma clearance* (*CLh,m*) - *Hepatic metabolic blood clearance* (*CLh,b,m*) - *Renal excretory plasma clearance* (*CLr*) ## **Extraction** - **Extraction ratio is the fraction of drug that is removed from the blood or plasma as it crosses the eliminating organ** - Limits are *0≤E≤1* - *No more drug can be eliminated than what is delivered to the organ* - *Unitless* ## (1) **Mass Balance Model** - *QxCA* = *Rate of entry (mg/min)* - *Qx(CA-Cv)* = *Rate of elimination (mg/min)* - *QxCv* = *Rate of output (mg/min)* - *Q* = *Blood flow* - *CA* = *Arterial drug concentration* - *Cv* = *Venous drug concentration* ## (2) **Divide Equation in (1) with Q.CA** - *Eliminating organ* = ( *CA* - *Cv* ) / *CA* = *E* ## **Divide Equations in (1) with CA** - *Eliminating organ* = *Q (1-E) / Q* = *CLbQE / CLb* = *CLh,r* + *CLh,H* + *CLh, others* = *QR* *x* *ER* + *QH* x *EH* + *Q others* x *E others* - *QR*= *Renal blood flow* ≅ *18% of cardiac output* ≅ *1.12L/min for 70 kg man* (Cardiac output is *6L/min*) - *QH*= *Liver blood flow* ≅ *22.5% of cardiac output* ≅ *1.35L/min for 70 kg man* - *Hepatic portal vein* ≅ *1050mL/min* (From spleen, pancreas, GI) - *Hepatic artery* ≅ *300mL/min* (From aorta) ## **Boundaries of CLb** - **When E is very high (close to 1)** - *Cout* ≅ *0* (Output concentration is very low) - *E* will approach unity (*E≅1*) - **Organ blood clearance becomes limited by blood flow** - **Flow-limited or perfusion-limited CL** - *E* = (*Cin-Cout*) / *Cin* - *CLb* = *QxE* ≅ *Q* - **When E is very small (e.g., <0.1)** - The drug is not extracted efficiently by the organ - *Cout* ≅ *Cin* - *E* is a very small number - **Organ blood clearance (CLb) is only a small fraction of blood flow (Q) and it is largely independent of blood flow** - **Capacity-limited *CL*** - *E* = (*Cin-Cout*) / *Cin* ≅ *small number* - *CLb* = *QxE* ≅ *0* ## **Hepatic Clearance** - *CLh* = *CLh,m* + *CLh, biliary* - **Metabolism is the clearance mechanism for approximately 73% of the top 200 drugs** - ~3/4 drugs metabolized by cytochrome P450 (CYP) superfamily - ~46% were by CYP3A family ## (ii) Describe factors affecting hepatic clearance - **Blood Flow (Qh)** - **Binding to blood cells (a)** - **Binding to plasma proteins (b)** (Fraction unbound drug, *fu*) - **Permeation or transport of unbound drug into hepatocytes (c)** - **Elimination via secretion into bile (d)** (Biliary clearance, *Clbiliary*) - **Elimination via metabolism (e)** (Intrinsic metabolic clearance, *Clint,m*) -*CLint,m* = *CLint, enzyme1* + *CLint, enzyme2* ## **Drugs with high *EH* (*EH≥0.7*)** - **Drug has high efficiency in:** - Partitioning out of blood cells - Dissociation from plasma proteins - Permeation trough hepatic membranes - Metabolism by hepatic enzymes - Biliary excretion into bile - **Organ blood clearance is hence limited by blood flow (flow-limited/perfusion-limited *CL*)** - Clearance is sensitive to changes in *QH* (blood flow), but relatively insensitive to changes in plasma protein binding or hepatocellular eliminating activity. ## **Drugs with Low EH (*EH<0.3*)** - Most common reasons for poor efficiency is that drug: - Is a poor substrate for the elimination process - Is polar and has inefficient lipophilicity to permeate readily into hepatocytes - Is substrate of efflux transporter along the sinusoidal (basolateral) membrane - *CLh* is not affected by *Qh* - Clearance is insensitive to changes in *Qh* but relatively sensitive to changes in plasma protein binding or hepatocellular eliminating activity. ## **Clinical application of EH** - Knowing whether a drug has a high *EH* (*>0.7*), intermediate *EH* (*0.3-0.7*), or low *EH* (*<0.3*) is important in predicting which factors (intrinsic clearance, protein binding, or blood flow) will alter the pharmacokinetic parameters for the drug. - Morphine, metoprolol, verapamil - Phenytoin, indomethacin, cyclosporin, amoxicillin, digoxin, atenolol - Codeine, midazolam, nifedipine, metformin, cimetidine - These physiological variables may be altered by disease (e.g., renal disease), genetic polymorphism, age (pediatric, geriatric), etc. ## (iii) Rationalize the contributions of glomerular filtration, tubular secretion, and tubular reabsorption in the nephron to renal clearance ### **Renal clearance** - Most water-soluble drugs and drug metabolites made more water soluble via oxidation or conjugation are typically eliminated by the kidneys. - The nephron is the functional unit of the kidney that is responsible for elimination of drugs. - Urine formation and renal clearance results from 3 processes: 1. **Glomerular filtration** 2. **Tubular secretion** 3. **Tubular reabsorption** - *Rate of excretion* = *(1-FR)* x *Rate of filtration* + *Rate of secretion* - *FR= fraction reabsorbed* - *Rate of excretion/C* = *(1-FR)* x *Rate of filtration/C* + *Rate of secretion/C* - *Rate of elimination/C* = *CLr* - *CLR=*(1-FR)* x* [CLf + (Ls)]* - *CLr*= *Renal plasma clearance*; *CLf*= *Renal filtration clearance*; *CLs*= *Renal secretory clearance* - If a drug is only filtered (0% secreted): *Rate of excretion* = *Rate of filtration* - *Rate of excretion/C* = *Rate of filtration* / *C* - *CLR* = *CLf* = *Fu* x *GFR* (&#x20;- *Fu*= unbound fraction; *GFR*= glomerular filtration rate*) - If only unbound drug in plasma water is filtered, protein-bound drug is too large pass through fenestration of glomerulus: - *Rate of filtration* (*mg/min*) = *GFR* (*mL/min*) x *Cu* (*mgmL*) - *Rate of filtration* (*mg/min*) = *Fu* x *GFR* (*mL/min*) x *C* (*mgmL*) ## **Renal Extraction Ratio, ER** - *E* = *Rate of extraction* / *Rate of presentation* - While filtration always occurs, the ER of a drug by filtration alone is low, and even lower when a drug is highly bound in plasma. - Some drugs have high ER due to tubular secretion. ## **High vs low extraction ratio drugs** | Hepatic Extraction | Low | Intermediate | High | |---|---|---|---| |Carbamazepine | Aspirin | Alprenolol | Meperidine | |Diazepam | Diazepam | Codeine | Nitrazepam | |Codeine | Buprofen | Cocaine | Ondansetrone | | Ibuprofen | Cyclosporine | Morphine | Paroxetine | |Cyclosporine | Meperidine | Nifedipine | Salicylic acid | |Meperidine | Nifedipine | Nortriptyline | | |Nifedipine | Nitrazepam | Nicotine | | |Nortriptyline | Ondansetrone | Nitroglycerin | | |Nicotine | Paroxetine | Valproic acid | | |Nitroglycerin | | Propoxyphene | | |Valproic acid | | Warfarin | | |Propoxyphene | | Verapamil | | ## **Renal Extraction** | | Low | Intermediate | High | |---|---|---|---| | Amoxicillin | Acyclovir | Metformin | Atenolol | | Acyclovir | Benzylpenicillin | | Benzylpenicillin | | Benzylpenicillin | Cefazolin | | p-Aminobenzoic acid | | Cefazolin | Cimetidine | | Cefazolin | | Cimetidine | | | Cephalothin | | Digoxin | | | Furosemide | | | | | Ciprofloxacin | | &nbsp; | | | Gentamicin | | &nbsp; | | | Ranitidine | | &nbsp; | | | Methotrexate | | &nbsp; | | | Pamidronate | ## (iv) Calculate PK parameters from plasma/serum/blood concentrations of a drug after a single IV bolus dose (PK profile follows one-compartment model) ### IV Bolus Administration - **Plasma (*C*) (mg/mL)** = 100, mono-exponential decline - **Rate of change in amount of drug in body: *dA/ dt=kx A* ** - ***C = Co* x*e-kt* ** - Upon integration to solve for *A* as a function of *t*: - ***A = (Ao)* x *e-kt*** - ***A = Dose* x *e-kt*** - Amount of drug at time =0 - ***y = mx + C* - *lnC* = *-kt* + *lnCo* - *Slope, k* is the elimination rate constant - Substituting *A = CxV*, - *C = Co* x *e-kt* - Taking natural logarithms: - *lnC* = *-kt* + *lnCo* - *lnC* = -*k*/*2.303* *t* + *lnCo* - Y-axis is a log scale, values not logged but distance between values are scaled ## **PK Parameters** 1. **Overall Elimination rate constant (*K*)** = (*lnC1-lnC2*) / (*t2-t1*) units: time^-1 2. **Elimination half-life (*t1/2*)*** = *ln2/k* units: time 3. **Apparent volume of distribution (*V*)** = *Ao/Co* = *Dose/Co* units: volume ## (4) **AUC0-∞** - Area under the plasma concentration-time curve from time *t*=0 to infinity (*AUC0-∞*) is the total systemic exposure. - **For IV bolus administration of a drug that follows one-compartment model with first-order elimination kinetics** - *C* = *Co* x *e-kt* - *AUC0-∞* = &#x20;∫₀^∞ *Coxe-ktdt* = *Co/k* = *Co/k* x *[0-1]* = *Co/k* - Units: *Concxtime* - Equation is only valid for the stated conditions: IV bolus, one-compartment, first-order elimination ## (5) **Total Clearance, CL** - **Rate of drug elimination:** *dA/ dt = CLxC* - **Rate of change of amount of drug in body:** *dA/ dt = -kxA = -kx CxV* - **Rate of drug elimination:** *dA/ dt = CLxC* - &#x20;Since *t1/2 = ln2/k* - *dA/ dt* = *CLxC* = *ln2xV/CL* *x* *C* - **On integration:** &#x20;∫₀^∞*-1/A* *dA* = ∫₀^∞*CL* *x* *C* *dt* - *A0* = *CL* x *∫₀^∞*C* *dt* - *A0* = *CL* x *AUC0-∞* - *Dose* = *CL* x *AUC0-∞* - **CL = Dose/AUC0-∞** units: *volume/time* ## (v) Differentiate and articulate the significance of primary vs secondary PK parameters ### **Primary PK Parameters** - Are independent of each other. - **V:** Is related to physiochemical properties of drug, plasma protein, and tissue protein binding. - **CL:** Is related to capacity and ability of cleaning organs to remove drug. - Each primary PK parameter may not be directly affected by changes in physiologic variables. - May be altered due to age, disease, concomitant drugs. | Primary Pharmacokinetic Parameter | Physiologic Variable | |---|---| | Absorption rate constant | Blood flow at absorption sites, rubbing, exercise (i.m. and s.c. administration), gastric emptying, transporters, intestinal motility (oral administration) | | Bioavailability | Gastric emptying rate, gastric acid secretion, biliary excretion of hydrolytic enzymes, intestinal motility, extraction in the gut wall and liver, transporters | | Hepatic clearance; bioavailability | Hepatic blood flow, binding in blod, intrinsic hepatocellular activity, enterohepatic cycling | | Renal clearance | Renal blood flow, binding in blood, active secretion, active reabsorption, urine pH, urine flow, glomerular filtration rate | | Volume of distribution | Binding in blood, transporters, binding in tissues, partitioning into fat, body composition, body size | **Hepatic elimination is assumed to be the only cause of a decrease in oral bioavailability.** ### **Secondary PK Parameters** - Value depends on those of primary PK parameters | Secondary PK Parameters | Dependence on Primary PK Parameters | |---|---| | *t1/2* (0.693*V/CL*) | Clearance, Volume of distribution | | *t1/2* (Renal clearance/Total clearance ) | Renal clearance, Total clearance | - Value depends on primary PK parameters AND dose - *AUC0-∞* (Dose/CL) - *Cmax* (Dose/Vol. of distribution) - *Amt excreted unchanged* (Dose x Renal clearance / Total clearance) ## **Impact of CL and V on t1/2** - **As CL increases, half-life decreases for a given V.** - **As V increases, half-life increases for a given CL.** &#x20; - **Half-life varies with changes in each parameter.** - **Half-life on its own is not a good index of body’s drug metabolizing or elimination capacity.** - **t1/2 may not change if V and CL change in the same proportion.** ## **Impact of CL and V on t1/2** - As *CL* increases, half-life decreases for a given *V*. - As *V* increases, half-life increases, for a given *CL*. - Half-life varies with changes in each parameter. - Half-life on its own is not a good index of body's drug metabolizing or elimination capacity. - *t1/2* may not change if *V* and *CL* change in the same proportion. ## (3L plasma volume) - *CL* (mL/hr) - *V* (L)