Drugs pharmacology in kidney disease

Editor's Notes

1. So, sodium bicarbonate is administered in ASA or phenobarbital overdose to increase the ionization of these drugs. This therapeutic intervention also reduces reabsorption by increasing urine flow.
2. Trapping of a weak base (pyrimethamine) in the urine when the urine is more acidic than the blood. In the hypothetical case illustrated, the diffusible uncharged form of the drug has equilibrated across the membrane, but the total concentration (charged plus uncharged) in the urine is almost eight times higher than in the blood.
3. Acidification of Urine Is used as a test for renal tubular acidosis Ref: Clinical pharmacology by Peter Bennett 2012
4. Alkalinisation of urine: Increases the elimination of salicylate, phenobarbital, and chlorophenoxy herbicides, e.g. 2,4-D, MCPA Sodium overload may exacerbate cardiac failure, and sodium or potassium excess are dangerous when renal function is impaired. Ref: Clinical pharmacology by Peter Bennett 2012
5. First-order (exponential) processes In the majority of instances, the rates at which absorption, distribution, metabolism and excretion of a drug occur are directly proportional to its concentration in the body. In other words, transfer of drug across a cell membrane or formation of a metabolite is high at high concentrations and falls in direct proportion to be low at low concentrations (an exponential relationship). Processes for which the rate of reaction is proportional to the concentration of participating molecules are first-order processes. In doses used clinically, most drugs are subject to first order processes of absorption, distribution, metabolism and elimination Zero-order processes (saturation kinetics) As the amount of drug in the body rises, metabolic reactions or processes that have limited capacity become saturated. In other words, the rate of the process reaches a maximum amount at which it stays constant, e.g. due to limited activity of an enzyme, and any further increase in rate is impossible despite an increase in the dose of drug. In these circumstances, the rate of reaction is no longer proportional to dose, and exhibits rate-limited or dosedependent 5 or zero-order or saturation kinetics. In practice, enzyme-mediated metabolic reactions are the most likely to show rate limitation because the amount of enzyme present is finite and can become saturated. Ref: Clinical Pharmacology 2012 by Peter Bennett
6. Fig. 8.2 Changes in plasma concentration following an intravenous bolus injection of a drug in the elimination phase (the distribution phase, see text, is not shown). As elimination is a first-order process, the time for any concentration point to fall by 50% (t½) is always the same. Order of reaction and t½. When a drug is subject to first order kinetics, the t½ is a constant characteristic, i.e. a constant value can be quoted throughout the plasma concentration range (accepting that there will be variation in t½ between individuals), and this is convenient. But if the rate of a process is not directly proportional to plasma concentration, then the t½ cannot be constant. Consequently, no single value for t½ describes overall elimination when a drug exhibits zeroorder kinetics. In fact, t½ decreases as plasma concentration falls and the calculations on elimination and dosing that are so easy with first-order elimination (see below) become more complicated. Ref: Clinical Pharmacology 2012 by Peter Bennett
7. When a drug is given at a constant rate (continuous or repeated administration), the time to reach steady state depends only on the t½ and, for all practical purposes, after 5 t½ periods the amount of drug in the body is constant and the plasma concentration is at a plateau Ref: Clinical Pharmacology 2012 by Peter Bennett
8. Alcohol (ethanol) is a drug whose kinetics has considerable implications for society as well as for the individual, as follows: Alcohol is subject to first-order kinetics with a t½ of about 1 h at plasma concentrations below 10 mg/dL (attained after drinking about two-thirds of a unit (glass) of wine or beer). Above this concentration the main enzyme (alcohol dehydrogenase) that converts the alcohol into acetaldehyde approaches and then reaches saturation, at which point alcohol metabolism cannot proceed any faster than about 10 mL or 8 g/h for a 70-kg man. If the subject continues to drink, the blood alcohol concentration rises disproportionately, for the rate of metabolism remains the same, as alcohol shows zero-order kinetics. An illustration. Consider a man of average size who drinks about half (375 mL) a standard bottle of whisky (40% alcohol), i.e. 150 mL alcohol, over a short period, absorbs it and goes drunk to bed at midnight with a blood alcohol concentration of about 250 mg/dL. If alcohol metabolism were subject to first-order kinetics, with a t½ of 1 h throughout the whole range of social consumption, the subject would halve his blood alcohol concentration each hour (see Fig. 8.2). It is easy to calculate that, when he drives his car to work at 08.00 hours the next morning, he has a negligible blood alcohol concentration (less than 1 mg/dL) though, no doubt, a hangover might reduce his driving skill. But at these high concentrations, alcohol is in fact subject to zero-order kinetics and so, metabolising about 10 mL alcohol per hour, after 8 h the subject has eliminated only 80 mL, leaving 70 mL in his body and giving a blood concentration of about 120 mg/dL. At this level, his driving skill is seriously impaired. The subject has an accident on his way to work and is breathalysed despite his indignant protests that he last touched a drop before midnight. Banned from the road, on his train journey to work he will have leisure to reflect on the difference between first-order and zero-order kinetics (though this is unlikely!). In practice. The example above describes an imagined event but similar cases occur in everyday therapeutics. Phenytoin, at low dose, exhibits a first-order elimination process and there is a directly proportional increase in the steady-state plasma concentration with increase in dose. But gradually the enzymatic elimination process approaches and reaches saturation, the process becoming constant and zero order. While the dosing rate can be increased, the metabolism rate cannot, and the plasma Ref: Clinical Pharmacology 2012 by Peter Bennett
9. ECF = extra cellular fluid Most acidic drugs bind to the bilirubin binding site on albumin. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson Albumin decrease occurs in: Nephrotic states (albumin is lost in the urine). Hypermetabolic states (stress, trauma, sepsis) in which protein breakdown exceeds protein synthesis. Liver disease (decreased synthesis of albumin).
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13. Comparison of free and total plasma phenytoin levels in a patient with normal renal function and a functionally anephric patient who are both treated with a 300-mg daily phenytoin dose and have identical CLint. Although free phenytoin levels are 0.8 mg/mL in both patients, phenytoin is only 84% bound (16% free) in the functionally anephric patient, compared to 92% bound (8% free) in the patient with normal renal function. For that reason total phenytoin levels in the functionally anephric patient are only 5 mg/mL, whereas they are 10 mg/mL in the patient with normal renal function. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson Phenytoin is an acidic, restrictively eliminated drug that can be used to illustrate some of the changes in drug distribution and elimination that occur in patients with impaired renal function. In patients with normal renal function, 92% of the phenytoin in plasma is protein bound. However, the percentage that is unbound or “free” rises from 8% in these individuals to 16% (or more) in hemodialysis-dependent patients. In a study comparing phenytoin pharmacokinetics in normal subjects and uremic patients, Odar-Cederl€of and Borga° [49] administered a single low dose of this drug so that first-order kinetics were approximated. The results shown in Table 5.3 can be inferred from their study. The uremic patients had an increase in distribution volume that was consistent with the observed decrease in phenytoin binding to plasma proteins. The three-fold increase in hepatic clearance that was observed in these patients also was primarily the result of decreased phenytoin protein binding. Although CLint for this CYP2C9, CYP2C19, and P–gp substrate also appeared to be increased in the uremic patients, the difference did not reach statistical significance at the P ¼ 0.05 level. A major problem arises in clinical practice when only total (protein-bound þ free) phenytoin concentrations are measured and used to guide therapy of patients with severely impaired renal function. The decreases in phenytoin binding that occur in these patients result in commensurate decreases in total plasma levels (Figure 5.3). Even though therapeutic and toxic pharmacologic effects are correlated with unbound rather than total phenytoin concentrations in plasma, the decrease in total concentrations can mislead physicians into increasing phenytoin doses inappropriately. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
14. PK = Pharmacokinetics ClE = elimination clearance (total clearance) ClCr = Creatinine clearance
15. Moderate renal insufficiency (creatinine clearance 10 to 50 mL/min.). Severe renal insufficiency (creatinine clearance < 10 mL/min.).
16. BMI =body mass index In oliguria (<500 mL/24 hrs), the creatinine clearance is less than 10 mL/min., regardless of the creatinine concentration.
17. ClE = elimination clearance (total clearance) The characterization of drug metabolism by a clearance term usually is appropriate, since the metabolism of most drugs can be described by first-order kinetics within the range of therapeutic drug concentrations
18. ClE = elimination clearance (total clearance) ClCr = Creatinine clearance Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
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20. A 67-year-old man had been functionally anephric, requiring outpatient hemodialysis for several years. He was hospitalized for revision of his arteriovenous shunt and postoperatively complained of symptoms of gastroesophageal reflux. This complaint prompted institution of cimetidine therapy. In view of the patient’s impaired renal function, the usually prescribed dose was reduced by half. Three days later, the patient was noted to be confused. An initial diagnosis of dialysis dementia was made and the family was informed that dialysis would be discontinued. On teaching rounds, the suggestion was made that cimetidine be discontinued. Two days later the patient was alert and was discharged from the hospital to resume outpatient hemodialysis therapy. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
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22. Nomogram for estimating cimetidine elimination clearance (CLE) for a 70-kg patient with impaired renal function. The right-hand ordinate indicates cimetidine CLE measured in young adults with normal renal function, and the left-hand ordinate indicates expected cimetidine CLE in a functionally anephric patient, based on the fact that 23% of an administered dose is eliminated by non-renal routes in healthy subjects. The heavy line connecting these points can be used to estimate cimetidine CLE from creatinine clearance (CLCR). For example, a 70-kg patient with CLCR of 50 mL/min (large dot) would be expected to have a cimetidineCLE of 517 mL/min, and to respond satisfactorily to doses that are 60% (517/850=0.6) of those recommended for patients with normal renal function. Reproduced with permission from Atkinson AJ Jr, Craig RM. Therapy of peptic ulcer disease. In: Molinoff PB, editor. Peptic ulcer disease. Mechanisms and management. Rutherford, NJ: Healthpress Publishing Group, Inc.; 1990. pp. 83–112 [9]. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
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24. Drug filtration rate = GFR*fu*[drug] (fu = free fraction) The proteins which actively transport drugs include: P-glycoprotein (P-gp), six multiple drug resistance proteins, five cation and nine organic anion transporters, along with a number of genetic variants Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
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26. Cl Cr = creatinine clearance Cl = clearance Ref: Principles Of Clinical Pharmacology By Arthur Atkinson Glomerulotubular balance (GTB) is defined as the ability of each successive segment of the proximal tubule to reabsorb a constant fraction of glomerular filtrate and solutes delivered to it. Ref: https://www.ncbi.nlm.nih.gov › pubmed
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28. Adequate renal function is a prerequisite for lithium therapy. In renal impairment, TDM for lithium must be done. Lithium and bromide are examples of drugs that are extensively reabsorbed by active transport mechanisms. Present evidence suggests that lithium is reabsorbed at the level of the proximal tubule by a Na /H exchanger (NHE-3) at the brush border and extruded into the blood by sodium–potassium ATPase and the sodium bicarbonate cotransporter located at the basolateral membrane. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
29. Net drug elimination is affected by drug reabsorption in the distal nephron, by passive diffusion. Proximal tubular endocytosis, mediated by the apical cell membrane receptors megalin and cipolin, plays an important role in removing proteins and peptides that pass through glomerular filtration pores [22]. This accounts for the absence of protein in normal urine and for the essential conservation of protein-carrier-bound vitamins and trace elements which are returned to the systemic circulation. However, the absorbed peptides and proteins are degraded by lysosomal proteases within the renal tubular cells. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
30. Most drugs are lipid soluble which aids their movement across cell membranes. The kidneys can excrete only water soluble substances. One function of metabolism is to convert fat soluble drugs into water-soluble metabolites. The kidney plays a major role in the clearance of insulin from the systemic circulation, removing approximately 50% of endogenous insulin and a greater proportion of insulin administered to diabetic patients. Insulin is filtered at the glomerulus, reabsorbed by the proximal tubule cell endocytotic mechanism described above, and then degraded by lysosomal proteolytic enzymes. Consequently, insulin requirements are markedly reduced in diabetic patients with impaired renal function. Imipenem and other peptides and peptidomimetics are also filtered at the glomerulus, absorbed by endocytosis, then metabolized by proximal renal tubule cell proteases [27]. Cilastatin, an inhibitor of proximal tubular dipeptidases, is co-administered with imipenem to enhance the clinical effectiveness of this antibiotic. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
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32. Hepatic drug clearance (CLH) is mediated by transporter uptake and excretion mechanisms, as well as by metabolic processes within hepatocytes. In some cases hepatocyte uptake is the rate limiting step in drug elimination, and the expression and uptake function of hepatic organic anion transport polypeptides (OATPs) has been shown to be depressed in an animal model of chronic renal failure whereas P-gp expression appeared to be increased. Impaired renal function impacts the hepatic clearance of drugs that are metabolized by a number of enzymatic pathways, as indicated in Table 5.2. Both Phase I biotransformations (cytochrome P450 (CYP) and non-CYP enzymes) and Phase II biotransformations (e.g., acetylation by NAT-2, glucuronidation by UGT2B) may be impaired to varying degrees, which are particularly pronounced in patients with end-stage renal disease (ESRD). The effects of impaired renal function on hepatic drug elimination have been attributed to the accumulation of 3–carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF), indoxyl sulfate, parathyroid hormone (PTH), cytokines, and perhaps other toxins that inhibit drug metabolism and transport. On the basis of experiments in rodent and in vitro models of chronic renal failure it has been shown that impairment occurs in some cases at the level of gene transcription, as indicated by decreased levels of the mRNA that encodes OATP2, a number of CYP enzyme, and NAT2 Ref: Principles Of Clinical Pharmacology By Arthur Atkinson An organic-anion-transporting polypeptide (OATP) is a membrane transport protein or 'transporter' that mediates the transport of mainly organic anions across the cell membrane. Therefore, OATPs are present in the lipid bilayer of the cell membrane, acting as the cell's gatekeepers. Ref: https://en.wikipedia.org/wiki/Organic-anion-transporting_polypeptide Important drug metabolizing phase I enzymes such as cytochrome P450 enzymes (CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and phase II enzymes n-acetyltransferase 2 (NAT2), UDP-glucuronosyltransferase (UGT), thiopurine S-methyltransferase (TPMT) are located in the liver. These enzymes are encoded by specific genes and polymorphism of such genes may inhibit or increase enzyme activity. Besides genetic polymorphism, environmental factors and concomitant drug intake can modulate the activity of drug metabolizing enzymes. In this context, drug interactions can occur indirectly mediated through genes. This covert gene-drug interaction is an area of great clinical importance and needs to be investigated in detail. NAT2 is located in the liver and catalyzes the acetylation of isoniazid (INH), hydralazine, sulphadoxine, procainamide, dapsone and other clinically important drugs. It also catalyzes the acetylation of aromatic and heterocyclic carcinogens. It is implicated in the modification of risk factors in the development of malignancies involving the urinary bladder, colorectal region, breast, prostate, lungs and the head and neck region. It is also shown to be involved in the development of Alzheimer's disease, schizophrenia, diabetes, cataract and parkinsonism Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989826/ NAT2 is one of only 2 N-acetyltransferase genes in humans; the other, NAT1, shows little variation between individuals, whereas NAT2 is known to have over 23 variants. N-acetyltransferases are enzymes acting primarily in the liver to detoxify a large number of chemicals, including caffeine and several prescribed drugs. Ref: https://www.snpedia.com › index.php › NAT2
33. CYP enzymes vary in their sensitivity to the adverse effects of impaired renal function, but that the extent of their impairment increases as renal function deteriorates. Relatively little information is available about the effects of impaired renal function on Phase II metabolic pathways. In an early study, Gibson et al. [37] found that NAT2-mediated procainamide acetylation in hemodialysis- dependent patients was reduced by 61% in phenotypic slow acetylators and by 69% in rapid acetylators. Subsequently, Kim et al. [38] reported that isoniazid acetylation by NAT2 was decreased by 63% in ESRD slow acetylators but by only 23% in rapid acetylators. Osborne et al. [39] have shown that Phase II metabolismofmorphine to formglucuronide conjugates is reduced by 48% in functionally anephric patients. More importantly, these patients accumulated much higher concentrations of the morphine-6-glucuronide metabolite that is a much more potent narcotic than morphine. Both of these factors account for the serious adverse events that have been reported in some patients with severely impaired renal function who have been treated with morphine Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
34. Effect of increasing degrees of renal impairment on hepatic clearance mediated by different CYP enzymes. Moderate impairment ¼ CLCR 30–59 mL/min, Severe impairment ¼ CLCR < 30 mL/min, ▬▬ ▬ ▬ ▬▬ CYP3A4, ▬▬ ▬▬ CYP2D6, ▬▬▬ CYP2C9, ▬ ▬ ▬ ▬ CYP1A2, ,,,, CYP2C19, ▬ ▬▬ ▬ ▬▬ CYP2C8. Figure based on data from Rowland Yeo K, Aarabi M, Jamei M, Rostami-Hodjegan A. Expert Rev Clin Pharmacol 2011;4:261–74 [36]. Ref: Principles Of Clinical Pharmacology By Arthur Atkinson
35. Ref: Clinical pharmacology by Peter Bennett 2012
36. PDA = patent ductus arteriosus
37. Probenecid is a uricosuric and renal tubular blocking agent.  Ref: Clinical pharmacology by Peter Bennett 2012
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41. Vd = volume of distribution Ref: Clinical pharmacology by Peter Bennett 2012
42. The time to reach steady-state blood concentration is dependent only on drug t½, and a drug reaches 97% of its ultimate steady-state concentration in 5 t½. Thus, if t½ is prolonged by renal impairment, so also will be the time to reach steady state. Ref: Clinical pharmacology by Peter Bennett 2012
43. drug effect relates to free (unbound) concentration at the tissue receptor site, which in turn reflects (but is not necessarily the same as) the concentration in the plasma. For many drugs, correlation between plasma concentration and effect is indeed better than that between dose and effect. Yet monitoring therapy by measuring drug in plasma is of practical use only in selected instances. The underlying reasons repay some thought. Ref: Clinical Pharmacology 2012 by Peter Bennett
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45. Potassium depletion The loop diuretics produce a smaller fall in serum potassium concentration than do the thiazides, for equivalent diuretic effect, but have a greater capacity for diuresis, i.e. higher efficacy especially in large dose, and so are associated with greater decline in potassium levels. If diuresis is brisk and continuous, clinically important potassium depletion is likely to occur. When a thiazide diuretic is used for hypertension, there is probably no case for routine prescription of a potassium supplement if no predisposing factors are Present Low dietary intake of potassium predisposes to hypokalaemia; the risk is particularly notable in the elderly, many of whom ingest less than 50 mmol per day (the dietary normal is 80 mmol).   Hypokalaemia may be aggravated by other drugs, e.g. b2-adrenoceptor agonists, theophylline, corticosteroids, amphotericin. Hyperkalaemia Ciclosporin, tacrolimus, indometacin and possibly other NSAIDs may cause hyperkalaemia with the potassium-sparing diuretics. Treatment of hyperkalaemia Depends on the severity and the following measures are appropriate: • Any potassium-sparing diuretic should be discontinued. A cation-exchange resin, e.g. polystyrene sulphonate resin (Resonium A, Calcium Resonium, see below) can be used orally (more effective than rectally), to remove body potassium by the gut. • Potassium may be moved rapidly from plasma into cells by giving: n sodium bicarbonate, 50 mL 8.4% solution through a central line, and repeated in a few minutes if characteristic ECG changes persist n glucose, 50 mL 50% solution, plus 10 units soluble insulin by i.v. infusion n nebulised b2-agonist, salbutamol 5–10 mg, is effective in stimulating the pumping of potassium into skeletal muscle. • In the presence of ECG changes, calcium gluconate, 10 mL of 10% solution, should be given i.v. and repeated if necessary in a few minutes; it has no effect on the serum potassium but opposes the myocardial effect of a raised serum potassium level. Calcium may potentiate digoxin and should be used cautiously, if at all, in a patient taking this drug. Sodium bicarbonate and calcium salt must not be mixed in a syringe or reservoir because calcium precipitates. • Dialysis may be needed in refractory cases and is highly effective. Hyponatraemia may result if sodium loss occurs in patients who drink a large quantity of water when taking a diuretic. Other mechanisms are probably involved, including enhancement of antidiuretic hormone release. Such patients have reduced total body sodium and extracellular fluid and are oedema free. Discontinuing the diuretic and restricting water intake are effective. The condition should be distinguished from hyponatraemia with oedema, which develops in some patients with congestive cardiac failure, cirrhosis or nephrotic syndrome. Here salt and water intake should be restricted because extracellular fluid volume is expanded. The combination of a potassium-sparing diuretic and ACE inhibitor can also cause severe hyponatraemia – more commonly than life-threatening hyperkalaemia. Urate retention with hyperuricaemia and, sometimes, clinical gout occurs with thiazides and loop diuretics. The effect is unimportant or negligible with the low-efficacy diuretics, e.g. amiloride and spironolactone. Two mechanisms appear to be responsible. First, diuretics cause volume depletion, reduction in glomerular filtration and increased absorption of almost all solutes in the proximal tubule, including urate. Second, diuretics and uric acid are organic acids and compete for the transport mechanism that pumps such substances from the blood into the tubular fluid. Diuretic-induced hyperuricaemia can be prevented by allopurinol or probenecid (which also antagonises diuretic efficacy by reducing their transport into the urine). Magnesium deficiency Loop and thiazide diuretics cause significant urinary loss of magnesium; potassium-sparing diuretics probably also cause magnesium retention. Magnesium deficiency brought about by diuretics is rarely severe enough to induce the classic picture of neuromuscular irritability and tetany but cardiac arrhythmias, mainly of ventricular origin, do occur and respond to repletion of magnesium (2 g or 8 mmol of Mg2þ is given as 4 mL 50% magnesium sulphate infused i.v. over 10–15 min followed by up to 72 mmol infused over the next 24 h). Calcium homeostasis Renal calcium loss is increased by the loop diuretics; in the short term this is not a serious disadvantage and indeed furosemide may be used in the management of hypercalcaemia after rehydration has been achieved. In the long term, hypocalcaemia may be harmful, especially in elderly patients, who tend in any case to be in negative calcium balance. Thiazides, by contrast, decrease renal excretion of calcium and this property may influence the choice of diuretic in a potentially calcium-deficient or osteoporotic individual, as thiazide use is associated with a reduced risk of hip fracture in the elderly. The hypocalciuric effect of the thiazides has also been used effectively in patients with idiopathic hypercalciuria, the commonest metabolic cause of renal stones. Interactions Loop diuretics (especially as intravenous boluses) potentiate ototoxicity of aminoglycosides and nephrotoxicity of some cephalosporins. NSAIDs tend to cause sodium retention, which counteracts the effect of diuretics; the mechanism may involve inhibition of renal prostaglandin formation. Diuretic treatment of a patient taking lithium can precipitate toxicity from this drug (the increased sodium loss is accompanied by reduced lithium excretion). Ref: Clinical pharmacology by Peter Bennett 2012
46. Renal drug handling. Drugs may be filtered from the blood in the renal glomerulus, secreted into the proximal tubule, reabsorbed from the distal tubular fluid back into the systemic circulation, and collected in the urine. Membrane transporters (OAT, OCT, MDR1, and MRP2, among others) mediate secretion into the proximal tubule (see Figures 5–12 and 5–13 for details). Reabsorption of compounds from the distal tubular fluid (generally acidic) is pH sensitive: Ionizable drugs are subject to ion trapping, and altering urinary pH to favor ionization can enhance excretion of charged species
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