Excretion

Excretion in Pharmacokinetics

Excretion, as you may be able to guess, is the final step in the pharmacokinetic. It involves the irreversible removal of drugs and metabolites from the body. For most drugs, this is carried out by the kidneys. The kidneys eliminate drugs and metabolites through several steps which ends in production of urine. A small number of drugs are excreted in the bile which is incorporated into the faeces. Minor routes of excretion include sweat, saliva, hair, nails, exhalation, breastmilk and tears.

Excretion should not be confused with clearance or elimination. These later concepts describe removal of drug from the blood by excretion plus transformation (ie metabolism).

Renal Excretion

The kidneys are the major excretory organs. They receive ~25% of cardiac output (~1.2 L/min) and process this blood to produce ~1–2 litres of urine daily. Renal drug excretion involves three processes occurring in the nephron: glomerular filtration, tubular secretion, and tubular reabsorption. The net effect of these three processes determines overall renal clearance.

Nephron Anatomy

The functional unit of the kidney is the nephron. A human kidney has ~1,000,000 nephrons which cannot regenerate; chronic nephrotoxicity (eg some drug toxicities) can cause permanent loss of kidney function.

A nephron consists of tubules containing filtrate (which will become urine) that run adjacent to capillaries. The parts of the tubules following the flow of filtrate are the glomerulus, proximal tubule, loop of Henle, and distal tubule. The distal tubules drain into the collecting duct which draws filtrate from several nephrons and drains into the ureters.

The process of creating urine, in the broadest sense, consists of the following:

• Most small, uncharged solutes diffuse from the blood into the filtrate at the glomerulus
• Sodium is concentrated in the filtrate at the loop of Henle
• Larger or charged solutes are pushed from the blood into the filtrate in the proximal tubule
• “good” solutes are reabsorbed from the filtrate back into the blood (eg amino acids, sugars, vitamins)

Glomerular Filtration

Glomerular filtration is the movement of drug (or any eligible solute for that matter) from the glomerular capillaries into Bowman’s capsule. The glomerular filtration barrier consists of fenestrated capillary endothelium, basement membrane, and podocyte foot processes. Since movement into Bowman’s capsule is by passive diffusion, the barrier is permeable only to small molecules (<20 kDa); passage of large proteins and protein-bound drugs is restricted.

Only unbound (free) drug can be filtered. Drugs extensively bound to plasma proteins (eg warfarin is 99% bound) have very little free drug available for filtration—excretion here will be very slow.

A rate of filtration can be derived from the patient’s intrinsic glomerular filtration rate (GFR). Filtration rate for a drug is given by the following equation:

$$ filtration\ rate = GFR \times f_u \times C_p $$

where, f_u is fraction unbound, and C_p is plasma drug concentration.

Glomerular Filtration Rate (GFR)

GFR is ~125 mL/min or ~180 L/day in most healthy adults but various factors may lead to decline in kidney function. GFR below 90 mL/min may be indicative of early kidney disease. In severe kidney failure, GFR may fall below 15 mL/min, a truly dangerous state for patients who take renally excreted drugs. It’s worth noting that GFR is not the only sign of kidney disease. GFR may be normal even when other markers show signs of kidney disease (eg proteinuria) and several acute reversible conditions can alter GFR even when there is no kidney disease (eg dehydration).

The list below gives some of the causes of reduced GFR

• Age (at a rate of ~1 mL/min/year beyond age 40)
• Diabetes
• Hypertension
• Glomerulonephritis
• Pyelonephritis
• Dehydration
• Many drugs (NSAIDs, tacrolimus, lithium)

GFR and a surrogate measure, creatinine clearance (CrCL) may be estimated using the CKD-epi or Cockcroft–Gault methods. These utilise a single blood test, serum creatinine, to estimate kidney function based on population averages for age, weight, sex, race etc. These estimates can help guide dosing adjustments for renally excreted drugs as discussed in Estimating Kidney Function below.

Tubular Secretion

Tubular secretion is the active transport of drugs from the capillaries surrounding the tubules into the tubular lumen. Most active secretion of drugs into the filtrate occurs in the proximal portion of the renal tubules. Active transport by carriers does the majority of tubular secretion. Carriers that contribute to tubular secretion can “strip” drug off plasma protein even if it is tightly bound. By this mechanism, tubular secretion can be significant for drugs that are bound to plasma proteins; glomerular filtration can only occur for unbound drug.

Two major transporter systems mediate tubular secretion: organic anion transporters (OATs) and organic cation transports (OCTs).

Substrates of the OAT and OCT systems.

Anionic drugs (substrates of OAT)	Catiotic drugs (substrates of OCT)
Penicillins and cephalosporins Loop diureticsfurosemide, bumetanide NSAIDS methotrexate probenacid	H2 blockerscimetidine, ranitidine metformin trimethoprim Class I antiarrhythmicslidocaine, procainamide, flecainide Platinum alkylating agentscisplatin, oxali’ Nueleoside-based antiviralslamivudine, zalcitabine, aciclovir, gancicl’, cidof’, tenof’ NMDA antagonistamantadine, memantine

The OAT system secretes acidic (anionic) drugs and uses an antiporter (exchanger) mechanism. The classical counterion for OATs is anodicarboxylic acid such as α-ketoglutarate. The OCT system secretes basic (cationic) drugs and uses a uniporter mechanism. These transporters are located on the basolateral (blood) side of proximal tubule cells.

On the apical (luminal) side of proximal tubule cells, our old friend P-glycoprotein effluxes drugs into the tubular lumen. P-glycoprotein secretes digoxin, loperamide, and many other drugs. These transporters work in concert with basolateral uptake transporters to achieve net secretion.

Tubular secretion is a saturable process. At high drug concentrations or when multiple substrates compete for the same transporter, secretion becomes saturated and clearance decreases. This is exploited therapeutically with probenecid, an OAT inhibitor that reduces penicillin secretion and prolongs penicillin half-life.

Tubular Reabsorption

Tubular reabsorption is the movement of drug from tubular lumen back into peritubular capillaries. Physiologically, this step serves to reclaim nutrients (eg glucose, amino acids, vitamins) that have been filtered and may be needed by the body. Reabsorption can occur passively via diffusion or actively via transport proteins. As a matter of convention, the fluid that was called “filtrate” earlier is called “tubular fluid” in this part of the nephron.

Passive reabsorption depends on the drug’s lipophilicity and ionisation state. As water is reabsorbed along the nephron, drug becomes more concentrated in tubular fluid, which could create a concentration gradient favouring reabsorption. Lipophilic, non-ionised drugs readily cross tubular epithelium and are reabsorbed easily, thus reducing renal clearance. Hydrophilic or ionised drugs cannot cross the membranes to return to the blood and therefore remain in tubular fluid to be excreted.

As you might predict, urine pH will significantly affect reabsorption of weakly acidic/basic drugs. Weak acids are non-ionised in acidic urine, facilitating reabsorption. Conversely, weak bases are non-ionised in alkaline urine, facilitating reabsorption. This principle can be used for helping to treat overdoses by enhancing excretion of the drug. Overdoses of acidic drugs (eg aspirin or phenobarbital) may be partially treated by alkalinising the urine with sodium bicarbonate. This is theoretically applicable to overdoses of basic drugs (eg amphetamine). Acidification using ascorbic acid was an old strategy in methamphetamine overdose but we now know it risks systemic acidosis and many of these patients are already at high risk of metabolic acidosis. Not a good idea!

Active reabsorption involves carrier-mediated transport from tubular lumen to blood. Glucose, amino acids, and some vitamins utilise this mechanism. Few drugs undergo active reabsorption. One notable example is lithium which competes with sodium for reabsorption by the Na⁺/H⁺ exchanger 3 (NHE3). This is clinically important because sodium depletion (hypOnatraemia) allows more lithium to be reabsorbed, increasing plasma concentration and risking lithium toxicity. Similarly, in hypERnatraemia, sodium will outcompete lithium for NHE3 causing less lithium reabsorption and reduced plasma concentration (therapeutic failure).

Renal Clearance (CL_R)

As discussed in Distribution, clearance (CL) is the volume of plasma completely cleared of drug per unit time. Renal clearance (CL_R), predictably is the portion of CL performed by the kidneys (remember, the liver is the other major clearance organ that clears drug by metabolism). CL_R reflects the net effects of filtration, secretion, and reabsorption. Mathematically, we can express this like so...

$$ CL_R = (filtration\ rate) + (secretion\ rate) - (reabsorption\ rate) $$

Or expressed per unit plasma concentration:

$$ CL_R = (GFR \times f_u) + CL_{secretion} - CL_{reabsorption} $$

Renal clearance can be measured by comparing the amount of parent drug (ie not metabolised) collected in the urine to the AUC in plasma:

$$ CL_R = \frac{amount\ excreted\ unchanged\ in\ urine}{AUC} $$

Since the filtration clearance can be given by GFR × f_u, we may want to compare this value to the CL_R we measure. This can help us understand whether there is net tubular secretion or reabsorption. If CL_R > GFR × f_u, net tubular secretion must be occurring. Similarly, if CL_R < GFR × f_u, net tubular reabsorption must be occurring. For example penicillins have CL_R 500–700 mL/min, far exceeding the typical GFR of ~125 mL/min. This indicates that penicillins must also be cleared by considerable secretion after the glomerulus.

Fraction Excreted Unchanged (f_e)

The fraction excreted unchanged represents the proportion of systemically available drug that is excerted into the urine as parent (unchanged) drug rather than as metabolites. It is calculated as the ratio of renal clearance to total clearance:

$$ f_e = \frac{CL_R}{CL_{total}} $$

Drugs with high f_e (ie >0.7) are predominantly eliminated by the kidneys and require substantial dose adjustment when patients have renal impairment. Examples include gentamicin (f_e ~0.95), atenolol (f_e ~0.9), gabapentin (f_e ~1.0), and many cephalosporins (f_e 0.7–0.9).

Drugs with low f_e (<0.3) are predominantly cleared by metabolic processes and may only require small dose adjustments in renal impairment. However, this should not be taken as a rule. There are many drugs which are extensively metabolised (ie low f_e) but are transformed into active metabolites which themselves may be excreted by the kidneys. Even though f_e suggests low renal clearance, dose adjustment may still be necessary in these cases. The classic example of this is morphine which has f_e ~0.05 due to extensive glucuronidation during Phase II metabolism. Morphine-6-glucuronide (important for analgesic effect of morphine) and morphine-3-glucuronide (important for some toxic effects of morphine) are both considered active metabolites and excreted by the kidneys. Dispite its low f_e, morphine may still cause severe toxicity in our patients with renal impairment.

Estimating Kidney Function

Accurate assessment of kidney function is essential for appropriate dosing of renally eliminated drugs. Direct measurement of glomerular filtration rate (GFR) using exogenous markers like inulin (gold standard), iohexol, or radioactive tracers ⁵¹Cr-EDTA, ⁹⁹mTc-DTPA, and ¹²⁵I-iothalamate are accurate and well-validated but are impractical for routine clinical use. Instead, kidney function is usually estimated by tracking an endogenous marker—almost always creatinine.

Why Creatinine as a Marker?

Creatinine is a waste product of creatine phosphate breakdown in muscle tissue. It has several features that make it an attractive marker of glomerular filtration capacity. It...

• is produced at a relatively constant rate
• is freely filtered at the glomerulus
• is not reabsorbed
• is endogenous (does not require administration of any exogenous tracer substance)
• undergoes minimal metabolism
• can be measured fairly inexpensively in serum samples

However, creatinine clearance is not a perfect marker of glomerular filtration because it undergoes some secretion in the proximal tubule by organic cation transporters (OCT2 and MATE). Therefore, creatinine clearance typically overestimates true GFR by 10–20%.

Another important limitation of creatinine is that, as a product of muscle metabolism, it is partially dependent on body composition. Bodybuilders with high muscle mass produce more creatinine than frail elderly patients with sarcopenia. Diet (ie meat) may also affect creatinine levels. Certain drugs which inhibit the tubular creatinine secretion through competition for OCT (trimethoprim, cimetidine, some HIV antiretrovirals), causing serum creatinine to rise without causing true kidney damage. Race, sex, and age all affect creatinine production which must be considered when interpreting creatinine-based kidney function estimates.

Creatinine Clearance (CrCL): Cockcroft–Gault Equation

Creatinine clearance can be measured directly by collecting all urine over 24 hours and measuring both urine creatinine concentration and serum creatinine, then applying the clearance equation CrCL = (Urinary_cr × urine volume) / Serum_cr. However, 24-hour urine collection is usually not too cumbersome and impractical for routine use. Enter the Cockcroft–Gault equation.

Cockcroft and Gault developed their equation in 1976 to estimate creatinine clearance based on one reading of serum creatinine along with the patient’s age, weight, and sex; no urine collection required. The equation (when using S_cr in μmol/L) is...

$$ CrCL = \frac{(140 - age) \times weight \times constant}{S_{cr}} $$

Where age is in years and weight is in kilograms. The constant is 1.23 for males and 1.04 for females. If using S_cr in mg/dL, the formula becomes:

$$ CrCL = \frac{(140 - age) \times weight \times [0.85\ if\ female]}{72 \times S_{cr}} $$

The Cockcroft–Gault equation estimates creatinine clearance—that is the volume of blood cleared of creatinine per minute. Because creatinine is secreted in the proximal tubule in addition to being filtered by the glomerulus, CrCL overestimates true GFR by 10–20%.

CrCL uses

Many drug dosing studies, package insert recommendations, clinical guidelines and renal dosing manuals have been developed using Cockcroft–Gault CrCL, not eGFR. Using the same methods as the underlying studies is necessary for harmonising our clinical practise with the evidence base. The most widely-used reference text for renal dosing is The Renal Drug Handbook which uses CrCL for recommending dosage adjustments.

Cockcroft–Gault is particularly useful for drug dosing, especially for narrow therapeutic index drugs where precise dosing is critical. It provides an estimate in mL/min (not normalized to body surface area), which better reflects the individual patient’s absolute clearance capacity. This is important because drug clearance is an absolute value (mL/min), not a normalized one.

However, CrCL (using the Cockcroft–Gault method) has several major limitations. Some of these can be understood based on the discussion above.

• Poor accuracy at extremes of body weight (obesity, cachexia, frailty, bodybuilders)
• Use of total body weight (which includes fat mass that doesn’t produce creatinine)
• Less accuracy in elderly patients
• No adjustment for race (unlike modern eGFR equations)
• Developed for white male patients who lived in the 1970s

CrCL and Drug Dosing

Drug dosing guidelines frequently use creatinine clearance for dosage adjustment in renal impairment. Here are some clinically important examples:

Gentamicin is an aminoglycoside antibiotic with f_e 0.8–0.9 (highly renally excreted). Patients who have impaired renal function will excrete gentamicin more slowly and thus require less frequent dosing. In these patients, a general dosage guide can be followed:

• CrCL >60 mL/min: dose every 24 hours
• CrCL 40–60 mL/min: dose every 36 hours
• CrCL 20–40 mL/min: dose every 48 hours
• CrCL <20 mL/min: dose every 48–72 hours or longer

Gentamicin also requires therapeutic drug monitoring to ensure adequate levels are achieved without causing toxicity. Hospitals will each have their own protocols for gentamicin dosing and monitoring that should be followed.

Enoxaparin, a low molecular weight heparin for treatment of venous thromboembolism, is usually given at a standard treatment dose of 1 mg/kg twice daily. However, if CrCL <30 mL/min, the dose must be reduced to 1 mg/kg once daily due to accumulation and increased bleeding risk.

Examples of important drugs that require dosage adjustment in renal impairment include:

• Aminoglycosides^{gentamicin, tobra’, amikacin}
• vancomycin
• Many cephalosporins^{cephalexin, cefuroxime, ceftriaxone, cefepime}
• Anticoagulants^{enoxaparin, apixaban, ravaro’}
• digoxin
• lithium
• Gabapentinoids^{gabapentin, pregabalin}
• metformin
• DPP-4 inhibitors^{linagliptin, saxa’, alo’, vilda’} except linagliptin
• Sulfonylureas^{glibenclamide, glimepiride, gliclazide}
• Opioids^{codeine, oxycodone, morphine, tramadol, tapentadol} except fentanyl, methadone, buprenorphine

Estimated GFR (eGFR): CKD-EPI Equation

Estimated GFR (eGFR) equations were developed to better estimate true glomerular filtration rate and to standardize chronic kidney disease (CKD) classification. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, published in 2009 and updated in 2021, is now the most widely recommended equation for eGFR calculation. The 2021 equation is:

For females with S_cr ≤0.7 mg/dL: eGFR = 142 × (S_cr/0.7)^-0.241 × 0.9938^age

For females with S_cr >0.7 mg/dL: eGFR = 142 × (S_cr/0.7)^-1.200 × 0.9938^age

For males with S_cr ≤0.9 mg/dL: eGFR = 142 × (S_cr/0.9)^-0.302 × 0.9938^age

For males with S_cr >0.9 mg/dL: eGFR = 142 × (S_cr/0.9)^-1.200 × 0.9938^age

The result is automatically normalized to a standard body surface area of 1.73 m² and expressed as mL/min/1.73m². eGFR is usually reported on usual blood test automatically so clinicians rarely calculate it themselves.

eGFR Uses

The CKD-EPI method which gives eGFR estimates true glomerular filtration rate more accurately than Cockcroft–Gault. It performs better across diverse populations, body sizes, and ages. The equation was developed and validated in large, diverse cohorts.

Rather than dosage adjustments, eGFR is primarily used for staging chronic kidney disease (CKD). CKD stages are defined by eGFR: Stage 1 (≥90 mL/min/1.73m² with kidney damage markers), Stage 2 (60–89), Stage 3a (45–59), Stage 3b (30–44), Stage 4 (15–29), and Stage 5 (<15, kidney failure). These standardized categories make communication, prognostication, and research more uniform.

In turn, eGFR may also be used for monitoring kidney function trends over time, assessing risk for kidney disease progression and determining eligibility for certain procedures or treatments (eg contrast imaging, certain chemotherapy regimens).

eGFR and Drug Dosing

It gets somewhat tricky here. eGFR is normalized to an average body surface area of 1.73 m², but drug clearance is not. A 50 kg elderly woman and a 100 kg young man might both have eGFR of 60 mL/min/1.73m², but their actual kidney clearance capacities differ substantially. The smaller elderly woman likely has true GFR around 45 mL/min, while the larger young man likely has true GFR around 80 mL/min (before normalization). For drug dosing purposes, we care about the absolute clearance, not the normalized value.

Most drug dosing studies and package inserts were developed using Cockcroft–Gault CrCL, not CKD-EPI eGFR. We cannot reliably substitute eGFR for CrCL in these dosing algorithms without the potential for under- or over-dosing our patients.

For very small or very large patients, "de-normalizing" eGFR to actual GFR by adjusting for the patient’s actual body surface area may improve drug dosing accuracy, though this adds complexity.

Dosing in Renal Impairment

Renal impairment reduces clearance of renally eliminated drugs. This potentially causes an accumulation of the drug in the body leading to side effects and toxicity if dosages aren’t adjusted. The degree of dosage adjustment depends principally on the fraction excreted unchanged (f_e) and the severity of renal impairment (indicated by CrCL).

For drugs with high f_e, dose reduction in proportion to GFR reduction is generally appropriate. If a patient’s GFR is 30 mL/min (25% of the normal 120 mL/min) and the drug is 100% renally eliminated (f_e=1.0), reducing the dose to 25% of normal or extending the dosing interval 4-fold maintains a similar steady-state concentrations.

We can devise an equation to systematise dosage adjustments:

$$ dose\ adjustment\ factor = 1 - [f_e \times (1 - \frac{GFR_{patient}}{GFR_{normal}})] $$

For example, if f_e = 0.6 (60% renally eliminated) and patient GFR is 30 mL/min (25% of normal 120 mL/min), the dose adjustment factor is 1 - [0.6 × (1 - 0.25)] = 0.55, suggesting the dose should be 55% of normal.

Biliary Excretion

After the kidneys, the liver is the second most important organ of drug excretion. It excretes some drugs and drug metabolites into the bile, which drains into the small intestine and is incorporated into the faeces. Biliary excretion is particularly important for large, polar molecules (molecular weight >500 Da) that cannot be efficiently filtered by the glomerulus in the kidneys. Heavy conjugated metabolites (drug glucuronides and sulfates) are examples.

Biliary excretion involves active transport via ATP-binding cassette (ABC) transporters on the canalicular membrane of hepatocytes. P-glycoprotein (ABCB1), multidrug resistance protein 2 (MDRP2, ABCC2), and breast cancer resistance protein (BCRP, ABCG2) are important ABC efflux transporters found here.

The amount of drug or metabolite excreted in bile varies widely. Some drugs are almost entirely excreted in bile (eg rifampicin), but many others undergo negligible biliary excretion.

Enterohepatic Recirculation

Enterohepatic recirculation is a phenomenon whereby drug excreted in the bile undergoes a second round of absorption after the bile is squirted into the small intestines. This cycle can repeat multiple times, prolonging drug exposure.

Drug–glucuronide conjugates are commonly involved in enterohepatic recirculation. The drug–glucuronide conjugate is excreted in bile, reaches the intestine, and is hydrolysed by a bacterial β-glucuronidase enzyme, releasing the parent drug. The now-lipophilic parent drug can be reabsorbed, re-enter portal blood, return to the liver, and be re-conjugated and re-excreted for a second time. This cycle prolongs drug half-life.

Enterohepatic recirculation can be recognised on plasma concentration-time curves as a secondary peak or occurring several hours after the initial peak as shown in the figure below. Examples of drugs exhibiting enterohepatic recirculation include morphine, diclofenac, indomethacin, mycophenolic acid, and levonorgestrel. The extent of recirculation can vary between individuals because gut bacteria (which is variable from person to person) express β-glucuronidase that facilitates enterohepatic recirculation.

Minor Routes of Excretion

Pulmonary Excretion

The lungs excrete volatile substances and gases such as general anaesthetic gases (sevoflurane, desflurane, isoflurane, nitrous oxide). Ethanol is also partially eliminated via the lungs (the basis for roadside breathalyser testing) The rate of pulmonary excretion depends on the drug’s volatility, blood/gas partition coefficient, and alveolar ventilation. Pulmonary excretion is most significant for drugs that are highly volatile and poorly soluble in the blood.

Excretion in Breast Milk

Drugs can be excreted into breast milk, potentially exposing nursing infants. Factors that increase excretion of drugs into the breasmilk include:

• Lipophilic (milk itself has high fat content so attracts lipophilic drugs)
• Minimal ionisation
• Low protein binding
• Low molecular weight

The milk-to-plasma ratio (M/P ratio) indicates the relative concentration in milk versus plasma. M/P >1 indicates concentration in milk, while M/P <1 indicates lower milk concentrations.

Most drugs have low M/P ratios (<1) and total infant exposure is small because milk volume is relatively low (~150 mL/kg/day). Some drugs may have low M/P ratio but affect the infant even at the low doses found in breastmilk. Concerning examples include lithium (M/P ~0.5, but toxic to infants), radioactive substances, cytotoxic drugs, and drugs of abuse. Many drugs are considered compatible with breastfeeding, and there are various excellent databases or hotlines that can be consulted for specific recommendations.

Other Minor Routes

Small amounts of drug are excreted in saliva and sweat. These routes contribute minimally to total elimination but can be useful for therapeutic drug monitoring as an alternative to painful blood draws. Examples include measuring anticonvulsant levels (phenytoin, carbamazepine) or lithium in saliva. Sweat excretion is negligible for most drugs but can be detected and is sometimes used in forensic toxicology (eg drug testing patches).

Drugs can appear in hair, and nails, though these routes contribute negligibly to elimination. However, hair analysis is useful in forensic toxicology for detecting long-term drug use because the drug incorporates into hair as it grows and remains detectable months after exposure.

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