When the kidneys secrete fewer hydrogen ions into the filtrate how would blood pH affected?

Renal Drug Elimination

The kidney is the primary organ responsible for the elimination of drugs and their metabolites. The development of renal function begins during early fetal development and is complete by early childhood (Fig. 73.3D andTable 73.5). Total renal drug clearance (CLrenal) can be conceptualized by considering the following equation:

CLrenal=(GFR+ATS)−ATR

where glomerular filtration rate (GFR), active tubular secretion (ATS), and active tubular reabsorption (ATR) of drugs can contribute to overall clearance. As for hepatic drug metabolism, only free (unbound) drug and metabolite can be filtered by a normal glomerulus and secreted or reabsorbed by a renal tubular transport protein.

Renal clearance is limited in the newborn because of anatomic and functional immaturity of the nephron unit. In both the term and the preterm neonate, GFR averages 2-4 mL/min/1.73 m2 at birth. During the 1st few days of life, a decrease in renal vascular resistance results in a net increase in renal blood flow and a redistribution of intrarenal blood flow from a predominantly medullary to a cortical distribution. All these changes are associated with a commensurate increase in GFR. In term neonates, GFR increases rapidly over the 1st few months of life and approaches adult values by 10-12 mo (Fig. 73.3D). The rate of GFR acquisition is blunted in preterm neonates because of continued nephrogenesis in the early postnatal period. In young children 2-5 yr of age, GFR may exceed adult values, especially during periods of increased metabolic demand (e.g., fever).

In addition, a relative glomerular/tubular imbalance results from a more advanced maturation of glomerular function. Such an imbalance may persist up to 6 mo of age and may account for the observed decrease in the ATS of drugs commonly used in neonates and young infants (e.g., β-lactam antibiotics). Finally, some evidence suggests that ATR is reduced in neonates and that it appears to mature at a slower rate than the GFR.

Altered renal drug clearance in the newborn and infants result in the different dosing recommendations seen in pediatrics. The aminoglycoside antibiotic gentamicin provides an illustrative example. In adolescents and young adults with normal values for GFR (85-130 mL/min/1.73 m2), the recommended dosing interval for gentamicin is 8 hours. In young children who may have a GFR >130 mL/min/1.73 m2, a gentamicin dosing interval of every 6 hr may be necessary in selected patients who have serious infections that require maintaining steady-state peak and trough plasma concentrations near the upper boundary of the recommended therapeutic range. In contrast, to maintain “therapeutic” gentamicin plasma concentrations in neonates during the 1st few weeks of life, a dosing interval of 18-24 hr is required.

1 Introduction

Drug excretion is the final step in the ADME (Absorption, Distribution, Metabolism, and Excretion) process and consists of a series of pathways that remove an administered drug and/or its metabolites from the body. Excreted drugs are either eliminated in their original, unmetabolized form, or they can be eliminated following metabolic biotransformation, as described in the preceding chapters. The metabolic biotransformation prepares drugs for excretion. Typically, more hydrophobic drugs are transformed into a more polar, water-soluble compound that is readily eliminated. As an example, the anti-epileptic drug phenytoin is a highly lipophilic compound. A series of metabolic transformations in the liver convert phenytoin to several inactive water-soluble metabolites that can then be excreted in the urine. In addition, excretion of a drug is dependent on intrinsic properties of the drug, such as pH and size. For example, weakly acidic drugs display increased excretion in basic urine, while weakly basic drugs are excreted more readily in acidic urine. Ionized drugs with a molecular weight greater than 300 g/mol can be actively secreted by the liver into bile. Genetic variation and underlying acute or chronic comorbidities can also impact drug excretion. Impaired kidney function or hepatic diseases that compromise biotransformation pathways may decrease drug excretion, which can result in drug accumulation and potential toxicity.

Total medication clearance is described by CL = CLk + CLh + CLother where CLk reflects kidney clearance, CLh reflects hepatic clearance, and CLother integrates all other sources such as extracorporeal clearance as with renal replacement therapy or metabolism by pH-dependent plasma esterases (Lea-Henry et al., 2018). As can be seen in the preceding equation, the main contributors to drug excretion are the kidneys and the liver. Water-soluble compounds are excreted primarily by the kidneys, while larger, more hydrophobic compounds are the responsibility of the liver. Secondary routes of excretion do exist (CLother), such as through breast milk, sweat, saliva, hair, and respiration. However, their contribution tends to be small. The following chapter will describe the various routes of excretion, the methods by which researchers and clinicians measure and model drug excretion, and how this information may be applied clinically.

Renal Excretion of Drugs

The kidneys are the most important organs for drug elimination for most agents. In the newborn, the most frequently used drugs, such as antimicrobial agents and caffeine in the premature neonate, are excreted by way of the kidney. Renal elimination of these drugs reflects and depends on neonatal renal function, which is characterized by a low glomerular filtration rate (GFR), low effective renal blood flow, and low tubular function (secretion and reabsorption) compared with that in the adult. The neonatal glomerular filtration rate is about 50% of the adult value and is greatly influenced by gestational age at birth. A term neonate has a glomerular filtration rate of 2-4 mL per minute per 1.73 m2, whereas the glomerular filtration rate at less than 34 weeks of gestation is about 0.7-0.8 mL per minute per 1.73 m2. The most rapid changes in renal function occur during the first week of life, but adult values are not reached until 6-12 months after birth in term neonates.14,27 As expected, it takes even longer for the GFR to reach adult values in preterm infants secondary to the smaller number of glomeruli present.14 Medications administered to the neonate can also cause a decrease in GFR and ultimately reduced elimination of concurrent drugs. For example, indomethacin inhibits prostaglandin synthesis, which leads to an increase in renal vascular resistance and thus a reduction in renal blood flow. The consequence of this is a decreased clearance of other medications such as gentamicin that are dependent on glomerular filtration for elimination.

Effective renal blood flow may influence the rate at which drugs are presented to and eliminated by the kidneys. Available data suggest that there is low effective renal blood flow during the first 2 days of life (34-99 mL per minute per 1.73 m2), which increases to 54-166 mL per minute per 1.73 m2 by 14-21 days and further increases to adult values of about 600 mL per minute per 1.73 m2 by age 1-2 years. These data are probably not applicable to premature infants with very low birth weight, particularly those who weigh less than 750 g at birth. It is assumed, pending definitive data, that the glomerular filtration rate and renal blood flow in these micronates are substantially lower than those in bigger premature infants, such as those who weigh more than 1000 g at birth. Nevertheless, renal function in these patients is highly variable and reflected in the highly variable body clearance of a number of commonly administered drugs.

Tubular secretion and reabsorption are also variable and immature in neonates. Tubular secretion approaches adult values by 7-12 months of age in term neonates, while reabsorption maturation is more gradual and continues through adolescence.27 In premature neonates, tubular function is even more limited. Drugs that require tubular secretion for elimination (e.g., furosemide, morphine) typically exhibit decreased clearance during the neonatal period.

9.6.4 Pharmacokinetics of Large Molecules

This chapter emphasized drug excretion mechanisms for small molecules, given that most medications fall into this category. It should be recognized, however, that peptide and protein therapeutics now constitute a substantial portion of the compounds under preclinical and clinical evaluation. Large molecule therapeutics represent promising approaches to treat a variety of diseases, but they also bring to light challenges to drug development scientists in terms of manufacturing drug delivery and bioanalysis. Additionally, large molecules have different pharmacokinetic profiles than conventional small molecule drugs. For example, peptide and protein drugs are cleared by the same catabolic pathways used to eliminate endogenous and dietary proteins. Although both the kidney and liver can metabolize proteins by hydrolysis, there is minimal clearance of protein therapeutics via conventional renal and biliary excretion mechanisms. You must recognize these differences when applying the principles and concepts presented in this chapter to large molecule therapeutics.

Drug Excretion

The excretion of active drugs or their metabolites is the process by which drugs are removed from the body. Drug excretion primarily occurs through the kidney and liver (seeFig. 45.2).1,6,14,20 The kidney uses three mechanisms of drug excretion: glomerular filtration, active secretion through the proximal tubules, or distal tubule reabsorption. Glomerular filtration is very low in the first few days after birth and increases with hemodynamic changes and improved renal perfusion. Glomerular filtration also increases with gestational age; preterm infants typically have delayed renal clearance and longer half-life compared to term infants.1,6,14,20 Disease states common in critically ill newborns such as neonatal encephalopathy, sepsis, acute kidney injury, and congenital heart disease all have been associated with reduced glomerular filtration and reduced drug excretion.

Tubular processes related to drug secretion and reabsorption are also important to renal elimination yet incompletely understood particularly in neonates. Drug secretion in the proximal tubules uses transport systems that typically eliminate organic anions. Secretion transporter proteins secrete drugs that are conjugated with glucuronic acid, glycine, and sulfate, such as penicillin or furosemide. Tubular secretion is less developed in newborns, thereby partially explaining the prolonged half-life of penicillin and furosemide.1,14,20 Membrane transporters in the distal tubule can actively reabsorb drugs from the tubular lumen back into the systemic circulation. Tubular reabsorption is also delayed in neonates. Glomerular filtration rate typically improves with maturation faster than tubular mechanisms.

The liver uses four mechanisms of drug excretion: drug metabolism, excretion into bile, fecal elimination, and enterohepatic recirculation. Hepatic drug elimination can be dependent on hepatic blood flow and the metabolic capacity of liver. Patients with hepatic insufficiency have decreased elimination of drugs because of alterations in protein levels and protein binding, decreased liver blood flow, decreased uptake into hepatocytes, and altered hepatic enzymatic reaction. Patients with hepatic insufficiency, however, exhibit marked variability in drug metabolism and elimination. Infants with hepatic insufficiency typically benefit from lower doses of drugs that are eliminated by hepatic biotransformation and therapeutic drug monitoring when possible.

Regardless of excretion mechanism, the rate at which drugs are eliminated from the circulation is essential to the PK properties of drug clearance (CL), elimination rate constant (Kel), and half-life (

Kidneys

•

The greatest proportion of drug excretion occurs through the kidneys.

The liver makes most drugs and remedies water soluble for removal via the kidneys (see Figure 17.1, p. 131).

One-fifth of the plasma reaching the kidney glomerulus is filtered through the pores in the glomerular cell membrane. The rest passes through the blood vessels around the renal tubules (Figure 18.1).

Substances with a low molecular weight and not bound to plasma proteins can easily pass through the cell membranes into the tubules.

Active secretion against a concentration gradient also takes place in the tubules.

The factors affecting the rate at which the drug or remedy is excreted by the kidneys are:

kidney disease

pH of urine

change in renal blood flow

concentration of drug or remedy in plasma

its molecular weight.

Terminology

Drug metabolism and excretion are profoundly affected by the size of various body fluid compartments. Fluid distribution among these compartments is significantly different in infancy and childhood, which in turn alters the action of certain drugs in this age group.

A brief review of body fluid nomenclature may be helpful at this point. The total body water space consists of the intracellular fluid (ICF) and extracellular fluid (ECF) compartments. The volume of distribution (Vd) is that volume into which a drug distributes in the body at equilibrium. Although Vd is usually measured in plasma (the volume of plasma at a given drug concentration that is required to account for all drug in the body), many drugs distribute into body tissues as well. Thus Vd may be estimated at many times the total plasma volume.

Excretion

Drug excretion is the removal of drugs from the body, either as a metabolite or unchanged drug. There are many different routes of excretion, including urine, bile, sweat, saliva, tears, milk, and stool. By far, the most important excretory organs are the kidney and liver. In kidney, excretion of drugs depends on glomerular filtration, active tubular secretion, and passive tubular absorption. Urine and blood pH and the physical characteristics of the drug molecule are important in determining whether the drug is excreted in the urine or remains in the circulation. Drugs appearing in bile will enter the intestines and may be reabsorbed resulting in enterohepatic circulation. Biliary excretion eliminates substances from the body only to the extent that enterohepatic cycling is incomplete. Drugs with a molecular weight (MW) exceeding 300 daltons and with polar and lipophilic groups are more likely to be excreted in bile. Clearance is a measure of the ability of the body to eliminate a drug. The elimination behavior of a drug is described most simply by its half-life, the time needed for the drugs concentration to be halved.

Maintenance

•

Impaired drug metabolism, detoxification, and excretion by the liver can prolong drug half-lives (volatile agents, muscle relaxants, analgesics, and sedatives may be affected).

Remifentail organ independent metabolism, fentanyl common choice

Cis/Atracurium are neuromuscular blockers of choice due to organ independent metabolism

Decrease dose 50% for morphine, meperidine, barbiturates, and benzodiazepines.

Desflurane most minimally metabolized inhalational agent; however, sevoflurane and isoflurane also shown to be safe in pts with impaired liver function. Factors known to reduce hepatic blood flow, such as hypotension, excessive sympathetic activation, and high mean airway pressures during controlled ventilation should be avoided

Technical losses of the model

While studying drug absorption, distribution, and excretion, it is important to include the various losses that are inherently included in a human-on-a-chip. At present most of the organs-on-chip are fabricated using silicones (PDMS) that are porous and elastomeric in nature [101]. Though the porous nature is beneficial for oxygenation of the cells cultured in them, it can lead to loss of drugs by retention and permeation, known as package loss of the effluents. Empirical relations that relate the surface area of channels, volume of PDMS used to make the organ-on-a-chip, and package loss have to be developed, for in vivo drug dosage extrapolation.