Excretion Phase Drug Interactions

Drug Interactions

Drug interactions occur when one drug’s pharmacokinetic, pharmacodynamic or toxicological characteristics are influenced by a second substance. Usually, the second substance is another drug—termed a “drug-drug interaction”—but it can also be a component of the diet (such as proteins, fats, minerals, vitamins). In describing these interactions we use the terms “victim” and “perpetrator”. The victim is the drug whose PK, PD or tox characteristics are changed whereas the perpetrator is the drug (or sometimes a nutrient) who causes the change. In many instances, both drugs are affected and the victim/perpetrator model breaks down.

Excretion Phase Drug Interactions Overview

Excretion phase drug interactions occur by mechanisms involving competition for renal tubular transporters, alterations in urine pH (affecting reabsorption by passive diffusion), or changes in renal blood flow. While generally less common than metabolic interactions, excretion interactions can be clinically significant. As always, this is particularly true for drugs with narrow therapeutic windows that are predominantly eliminated unchanged by the kidneys.

The clinical significance of an excretion interaction depends on the fraction of victim drug excreted unchanged (f_e), the therapeutic index of the victim drug, and the potency of the perpetrator in affecting excretion. Drugs with high f_e (>0.7) that are predominantly renally eliminated are highly susceptible because non-renal routes of clearance (eg metabolism) cannot adequately clear the drug if renal function becomes compromised in some way. Drugs with narrow therapeutic windows (eg digoxin, methotrexate, lithium, aminoglycosides and vancomycin) pose serious risk of toxicity when excretion is impaired.

Competition for Renal Tubular Transporters

The most interesting excretion interactions involve competition for renal tubular secretion transporters. When two drugs are both substrates for the same transporter, they compete for binding and transport, potentially reducing clearance of one or both drugs.

Organic Anion Transporter (OAT) Interactions

As discussed in Excretion, the OAT system in the proximal tubule secretes acidic drugs. These include penicillins, cephalosporins, fluoroquinolones, loop diuretics, NSAIDs, methotrexate, and uric acid. Competition for OAT can reduce secretion, increase plasma concentrations, and potentially cause toxicity.

Probenecid is a classic OAT inhibitor. It was used historically when penicillin was difficult and expensive to purify. Administration of probenacid would slow renal excretion of penicillin and extend its half-life and allowing less frequent dosing. Probenecid also inhibits secretion of other OAT substrates including cephalosporins, NSAIDs, and methotrexate. While the penicillin-probenecid combination is now rarely used (superseded by longer-acting beta-lactams), probenecid remains clinically useful for gout treatment so clinicians should remain vigilant for excretion phase interactions.

NSAIDs and methotrexate represents one of the most clinically significant OAT-mediated interactions. Methotrexate is secreted via OAT2 and OAT3. NSAIDs competitively inhibit methotrexate secretion, reducing renal clearance and increasing plasma concentrations. Additionally, NSAIDs can reduce renal blood flow via prostaglandin inhibition, further impairing methotrexate elimination. The combination can cause severe methotrexate toxicity including bone marrow suppression, mucositis, hepatotoxicity, and nephrotoxicity. This interaction is particularly dangerous with high-dose methotrexate (eg in cancer chemotherapy) and those patients should avoid NSAIDs. For low-dose methotrexate (eg used in rheumatoid arthritis), the interaction is less severe but still warrants monitoring.

Organic Cation Transporter (OCT) Interactions

As discussed in Excretion, the OCT system secretes basic drugs including metformin, cimetidine, ranitidine, procainamide, trimethoprim, and memantine. OCT-mediated interactions are generally less clinically significant than OAT interactions, but a few are noteworthy.

Cimetidine is both an OCT substrate and a competitive inhibitor. It inhibits secretion of other cationic drugs such as procainamide, metformin, and trimethoprim. Cimetidine plus procainamide can increase plasma concentrations of procainamide and its active metabolite N-acetylprocainamide, potentially causing QT prolongation and arrhythmias. These interactions contributed to cimetidine falling out of favour with clinicians compared to modern H₂ blockers such as ranitidine, nizatidine and famotidine.

Trimethoprim inhibits OCT2 and reduces creatinine secretion (creatinine is also secreted via OCT2). This causes a rise in serum creatinine without actual change in GFR—a “pseudo-renal impairment”. The increase is typically 10–20% and occurs within days of starting trimethoprim. This can complicate assessment of kidney function in patients on trimethoprim (including the combination product co-trimoxazole). Importantly, trimethoprim doesn't actually impair kidney function in this scenario; it only reduces creatinine secretion, making serum creatinine a less reliable marker of GFR. Similar pseudo-renal impairment occurs with cimetidine and the HIV drugs dolutegravir and cobicistat.

Dofetilide, a class III antiarrhythmic with narrow therapeutic window, is secreted via OCT and other cation transporters. Cimetidine, trimethoprim, verapamil, and ketoconazole are contraindicated with dofetilide due to risk of excessive QT prolongation and torsades de pointes tachyarrhythmia.

Renal P-glycoprotein Interactions

P-glycoprotein (P-gp) in the proximal tubule apical membrane contributes to secretion of several drugs. Elsewhere in the body (eg intestines, brain), P-gp is extremely important for transport across membranes and hence interactions involving P-gp can be very impactful. In the kidneys, P-gp is generally much less important because it is just one of several transporters involved in renal clearance. Since the contribution of P-gp is mild, the reduction in renal clearance caused by interactions involving this transporter are also comparatively small.

Digoxin is a P-glycoprotein substrate secreted in the proximal tubule. P-glycoprotein inhibitors including quinidine, verapamil, amiodarone, clarithromycin, and itraconazole reduce digoxin renal clearance causing extended half-life. Together with effects on P-glycoprotein-mediated tissue distribution (discussed in Distribution Phase Drug Interactions), these interactions typically increase digoxin concentrations 50–100%. It is a fairly well-accepted recommendation to halve digoxin dose when starting a P-glycoprotein inhibitor. As always for digoxin, therapeutic drug monitoring is critical.

Urine pH Alterations

Several drugs may alter the pH of urine. They therefore alter ionisation of weakly acidic/basic drugs in the urine which in turn affects passive reabsorption. We discussed in Excretion how this mechanism can be taken advantage of therapeutically in overdose management. It can also cause unintended drug interactions. Usual pH of urine is 6.0–7.5.

Urine Alkalinisation

Alkalinising the urine (increasing pH to 7.5–8.5) with sodium bicarbonate or acetazolamide causes weak acids to be mostly ionised, trapping them in tubular fluid and boosting their excretion. This is used therapeutically in aspirin and phenobarbital overdoses to accelerate elimination.

However, urine alkalinisation can have unintended effects. Amphetamines are weak bases that become non-ionised in alkaline urine, enhancing reabsorption and reducing clearance. Use of antacids or sodium bicarbonate is a strategy used by recreational users to prolong amphetamine effects by reducing excretion. It may instead increase toxicity risk and overdose.

Quinidine, also a weak base, is more readily reabsorbed in alkaline urine. Antacids or sodium bicarbonate can reduce quinidine clearance, potentially causing toxicity (such as QT prolongation, torsades de pointes, cinchonism). Conversely, acidifying the urine increases quinidine excretion.

Urine Acidification

Acidifying the urine (decreasing pH to 5.5–6.5) with ammonium chloride or ascorbic acid ionises weak bases, enhances excretion of weakly basic drugs . This was historically used in amphetamine and phencyclidine (PCP) overdoses but is now rarely used due to the risk of systemic acidosis.

Methenamine, a urinary antiseptic, is metabolised into formaldehyde in acidic urine for antibacterial effect. Urine acidifiers like ascorbic acid enhance methenamine's efficacy, while alkalinising agents (such as sodium bicarbonate used to relieve burning in urinary tract infections) reduce it. This represents an intentional pH-dependent interaction.

Renal Haemodynamic Interactions

The relationship between organ clearance and organ perfusion was discussed in Distribution. Clearance is proportional to organ blood flow (Q) and extraction ratio (E). For renal clearance, this is given by the following equation.

$$ CL_{renal} = Q_{renal} \times E_{renal} $$

Accordingly, when renal blood flow is altered due to a drug effect, the glomerular filtration of other drugs can also be affected. As a broad rule, any drug with renal haemodynamic effects may contribute to such drug interactions.

NSAIDs and Renal Function

Non-steroidal anti-inflammatory drugs (NSAIDs) act by blocking prostaglandin synthesis via COX-1 and COX-2 inhibition. Prostaglandins are conventionally considered mediators of inflammatory pain in inflammation; NSAIDs lessen this type of pain. In the kidneys, prostaglandins also work to dilate the arteriole that arrives at the glomerulus (afferent arteriole), increasing blood flow to the glomerulus and and preserving GFR. This mechanism is particularly important when arterial volume is reduced (eg in heart failure, volume depletion, cirrhosis, chronic kidney disease dehydration). Therefore, NSAIDs—which inhibit prostaglandin synthesis—constrict the afferent arteriole, reducing renal blood flow and GFR. Clearance of renally-eliminated drugs is decreased. As you might expect, this effect of NSAIDs is more pronounced when the patient already has low arterial perfusion due to volume depletion. We often recommend patients avoid NSAIDs if they have heart failure, are dehydrated or already have compromised renal function (CKD).

Through this mechanism, NSAIDs can reduce clearance of renally-eliminated aminoglycosides (gentamicin, tobramycin), potentially increasing nephrotoxicity and ototoxicity risk.

ACE Inhibitors and Renal Excretion

ACE inhibitors (and ARBs to a lesser extent) cause dilation of the exitting glomerular arteriole (efferent arteriole). This decreases pressure inside the glomerulus and hence there is less force pushing solutes into the filtrate; GFR is decreased. In patients with conditions that greatly reduce renal function (eg bilateral renal artery stenosis, advanced chronic kidney disease), these drugs can cause significant GFR reduction, further impairing clearance of renally eliminated drugs.

A particularly severe interaction can occur when ACE inhibitors are used together with a NSAID. In this combination there is simultaneous restriction of glomerular input (caused by NSAID-induced afferent arteriole constriction) and low glomerular pressure (caused by ACI inhibitor-induced efferent arteriole dilation). The result is very low GFR. If a diuretic is also used—causing volume depletion and further reduction in glomerular efficiency—acute kidney injury may occur.

Biliary Excretion Interactions

Interactions affecting biliary excretion are uncommon but can occur through competition for canalicular transporters or interference with enterohepatic recirculation.

MRP2 and BCRP Interactions

Multidrug resistance protein 2 (MRP2) and breast cancer resistance protein (BCRP) mediate biliary excretion of many drug–glucuronide and drug–sulfate conjugates. Inhibition of these transporters can reduce biliary clearance and increase systemic exposure. Ciclosporin, probenacid and glycyrrhizin inhibit MRP2, reducing biliary excretion of some drugs and metabolites such as the irinotecan active metabolite (SN-38), methotrexate, pravastatin, and fexofenadine. Eltrombopag, curcumin, omecamtiv, and elacridar inhibit BCRP, reducing biliary excretion of some drugs including some statins, sulfasalazine, and many tyrosine kinase inhibitors (eg imatinib, gefitinib). For example, irinotecan’s cytotoxic active metabolite, SN-38, is partially cleared by biliary clearance via the MRP2 system. When irinotecan is given together with a MRP2 inhibitor, patients excrete less active drug into the intestines and so are at lower risk of the gastric side effects (delayed diarrhoea) but slightly higher risk of systemic toxicity. However, these interactions are generally less clinically significant than renal transporter interactions because alternative elimination pathways often compensate.

Interruption of Enterohepatic Recirculation

Drugs that interfere with enterohepatic recirculation can enhance elimination of drugs normally recycled. Cholestyramine, a bile acid sequestrant, binds drugs in the intestinal lumen, preventing reabsorption. This is exploited therapeutically in digoxin overdose—cholestyramine binds digoxin in the gut, interrupting enterohepatic and enteroenteric recirculation (digoxin is secreted into the GI tract and normally reabsorbed) and accelerating elimination. Similar approaches are used for levothyroxine overdose.

An important step in enterohepatic recirculation is cleavage of drug–glucuronide conjugate back into the parent drug. This step is often carried out by a bacterial β-glucuronidase enzyme. When broad-spectrum antibiotics are used, gut bacteria are killed and cannot complete this step of enterohepatic recirculation. This mechanism was proposed to explain oral contraceptive failure with use of broad-spectrum antibiotics. Supposedly, reduced enterohepatic recirculation of ethinylestradiol–glucuronide would decrease ethinylestradiol exposure. However, clinical studies show this mechanism is less important than initially thought; patients using oral contraception routinely take many types of antibiotics safely.

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