Drug absorption

Pulmonary, GI, and peripheral blood flow changes during pregnancy can alter absorption of drugs from the lungs, gut, and skin (see Chapters 9, 10, and 12). The increased minute ventilation that occurs in pregnancy can increase the rate of drug uptake across the alveoli.^81,86 As a result, the pulmonary system may have a greater role in drug and metabolite excretion during pregnancy.⁹¹ Alveolar uptake of inhalation agents is also influenced by changes in cardiac output, which leads to increased pulmonary blood flow and thus increased alveolar uptake. As a result, doses of volatile anesthetics (e.g., halothane, isoflurane, methoxyflurane) may need to be decreased to compensate for these changes in the pregnant women.^81,102 Inhaled aerosols such as anti-inflammatory and bronchodilators may have enhanced absorption.¹⁰⁶

Absorption of oral medications is influenced by gastric acidity, gastric motility, presence of bile acids or mucus, nausea and vomiting of pregnancy, and intestinal transit time. During pregnancy there is decreased gastric acid (hydrochloric acid [HCl]) secretion, altered intestinal emptying time, increased mucus, and decreased gastric and intestinal motility.^36,106 Decreased gastric motility can increase the oral bioavailability of slowly absorbed drugs (such as digoxin) by prolonging transit time, and can decrease peak plasma levels of rapidly absorbed drugs. Factors altering GI function in pregnancy may initially delay, then prolong absorption of oral medications. Peak plasma levels may be lower, and the time to peak levels may be later than in nonpregnant women. These changes tend to peak in the third trimester.⁶⁸ Changes in pH affect ionization, and absorption of drugs.^36,81 For example, decreased gastric pH slows the rate at which weak acids (e.g., aspirin) are absorbed and increases absorption of weak bases (e.g., narcotic analgesics).¹⁰² Decreased GI motility may alter initial absorption of oral antibiotics and lead to unpredictable patterns of intestinal absorption. Absorption of hydrophilic drugs may be enhanced due to the longer intestinal transit time (from delayed intestinal emptying and decreased motility).⁸³ Increased cardiac output and peripheral blood flow may increase the rate of absorption of drugs from the stomach and small intestine.⁷⁸ Iron chelates with some drugs taken concurrently, preventing absorption. However, even with these changes in GI function, the clinical effect for most drugs is not significant. This is because therapeutic windows are usually wide enough for drugs administered orally that these factors do not significantly alter therapeutic effects.⁹¹

Cardiovascular and integumentary changes during pregnancy may lead to more rapid absorption of agents delivered via transdermal, intranasal, intravascular, epidural, and subcutaneous routes.¹⁰² The increased extracellular water and peripheral blood flow to the skin during pregnancy may enhance absorption and alter distribution of topical agents. For example, topical and vaginal iodine-based preparations are not recommended during pregnancy because of the increased absorption of iodine. Iodine is of concern because it is actively transported across the placenta to the fetus, whose thyroid gland has a high avidity for this substance (see Chapter 19). Increased peripheral perfusion secondary to decreased peripheral vascular resistance and vasodilation may increase absorption of intramuscular drugs.³⁶

Drug distribution

The distribution of drugs within the body depends on many factors, including the amount of body water, which affects Vd; degree to which a drug is bound to plasma proteins or body tissues; and the presence of the fetal-placental unit. For many drugs the Vd is increased during pregnancy because of the increased plasma volume, blood volume, cardiac output, total body water, and body mass.^20,36,91 The increased plasma and blood volumes, and thus Vd, may result in decreased drug levels in the central compartment, reduce serum levels of drugs, and necessitate larger loading doses.^83,103 Increases in total body water during pregnancy affect primarily water-soluble (polar) drugs that tend to stay in the extracellular space. Initial doses may need to be increased to achieve therapeutic concentrations; however, maternal doses for most drugs are not significantly altered since drug steady state is influenced by bioavailability and clearance as well as Vd.⁶⁸ Due to changes in the Vd, some pregnant women may notice that their prepregnancy dose of a drug taken regularly, such as digoxin or phenytoin, may not achieve the same therapeutic effect during pregnancy.

Some lipid-soluble drugs (e.g., caffeine, diazepam, thiopental) have a longer half-life in the pregnant woman, whereas polar drugs (e.g., oxazepam, ampicillin) tend to have a shorter half-life.^52,130 The Vd for lipophilic drugs is increased during pregnancy because of the accumulation of fat, which may serve as a reservoir for some drugs via tissue binding.^36,78 Tissue binding is a mechanism by which a drug is removed from circulation and stored in tissue such as hair, bone, teeth, and adipose tissue. This mechanism can result in storage of significant quantities of a drug, because tissue storage sites may need to be saturated before there is sufficient free drug to be effective at receptor sites. Factors reducing maternal serum drug levels increase the risk of subtherapeutic drug levels. When the drug is discontinued, tissue deposits may give up their stores slowly, resulting in persistent drug effects. Because lipid-soluble drugs are stored in adipose tissue, the increased adipose tissue during pregnancy can lead to a slight decrease in the amount of free lipid-soluble drugs, such as sedatives and hypnotics, and persistence of drug effects (“hangover”) after the drug has been discontinued.

Drugs in plasma are either unbound (free) or bound to plasma proteins, primarily albumin or α1-acid glycoprotein. The reduction in plasma proteins, especially albumin, during pregnancy may increase plasma levels of free (active) drug. Albumin is the major binding protein for acidic drugs such as salicylates, anticonvulsants, nonsteroidal anti-inflammatory agents, and some neutral drugs such as warfarin and diazepam.⁸¹ Serum albumin levels fall during pregnancy, increasing the unbound or free drug fraction. Total plasma drug concentration stays the same during pregnancy, but the unbound fraction of albumin-bound drugs is greater; therefore the drug may be cleared faster or transported more rapidly across the placenta.⁸¹ Increases in free drug do not necessarily lead to an increase in plasma levels of that drug if the increase in free drug is balanced by more rapid hepatic biotransformation or renal elimination.^36,81,102 However, with regard to doses of some drugs that are bound to albumin (such as many antiepileptic drugs), total and free drug concentrations may be altered, and doses may need to be adjusted during pregnancy. For example, phenytoin total plasma concentration is decreased by 55% to 65% and levels of free drug by 18% to 31% during pregnancy; carbamazepine total concentration is reduced 0% to 43% and free drug 0% to 28%; phenobarbital total concentration is reduced by 50% to 55%.¹⁰² Thus when monitoring serum concentrations of drugs such as phenytoin during pregnancy, free versus total levels should be evaluated (many laboratories report free levels if specified when ordering).³⁶

Free fatty acids and steroid hormones, both of which are increased in pregnancy, may compete with drugs for albumin binding sites, further increasing levels of unbound drug. The decrease in albumin, coupled with increases in free fatty acids and steroid hormones, are most prominent in late pregnancy. This change can result in unpredictable transient increases in free levels of some drugs, such as phenytoin, valproate acid, carbamazepine, sulfisoxazole, theophylline, and phenobarbital as well as the potential for more rapid elimination increases the risk of subtherapeutic maternal levels.^36,46 α1-Acid glycoprotein is the major protein for binding basic drugs such as local anesthetics, most opioids, and β-blockers. α1-Acid glycoprotein is decreased slightly during pregnancy.^6,106

Changes in protein binding during pregnancy not only influence availability of free drug in the mother but also the amount of drug available to cross the placenta. This may alter fetal-to-maternal drug ratios, thus further altering placental transfer. Drugs with hepatic blood flow–limited biotransformation (e.g., propranolol, lidocaine) are rapidly eliminated in their first pass through the liver, regardless of whether they are bound or unbound.^20,103 Therefore even with the decreased protein binding in pregnancy, hepatic clearance and total drug concentration generally are not significantly altered, although concentrations of free drug, Vd, and half-life may increase. Conversely, with drugs whose hepatic biotransformation is independent of hepatic blood flow (e.g., warfarin, phenytoin), only the unbound fraction is removed by the liver. For these drugs, total drug concentrations may be lower than usual, with a decreased half-life and greater fluctuations in peak and trough levels.

Hepatic drug metabolism

The hepatic changes during pregnancy (see Chapter 12) can alter biotransformation of drugs by the liver and clearance of drugs from the maternal serum. Drugs that are primarily (greater than 70%) metabolized in their first pass through the liver (high extraction ratio) are usually cleared rapidly by the liver, because clearance of these drugs is dependent on hepatic blood flow. Hepatic elimination of drugs with high extraction ratios is generally unchanged in pregnancy. Drugs with low (less than 30%) first-pass hepatic clearance (low extraction ratio) are more dependent on liver enzyme systems. The rate of elimination of these drugs (e.g., theophylline, caffeine, and diazepam) is related to free drug levels and tends to be decreased in pregnancy with increased half-lives. Hepatic elimination of other drugs—including many antibiotics, pancuronium, phenytoin, and acetaminophen—is increased in the pregnant woman.

Some liver enzymatic processes may be slower during pregnancy, delaying drug metabolism and degradation; other processes have increased activity. The cytochrome P450 (CYP450) monooxygenase system is a group of phase I enzymes essential for hepatic metabolism of drugs. The enzymes of this system are indicated by the prefix CYP (cytochrome) followed by a series of numbers and letters, (e.g., CYP1A2, CYP3A4, CYP2D6). Activity of the following are increased during pregnancy: CYP3A4 (50% to 100%), CYP2A6 (54%), CYP2D6 (50%), and CYP2C9 (20%).^5,57,72,123 Up regulation of CYP2C9 decreases plasma concentrations and increases clearance of phenytoin, nonsteroidal anti-inflammatory agents and some oral antidiabetic agents.^57,68 Changes to CYP3A4 may increase the metabolism of methadone, nifedipine, and indinavir during pregnancy.^102,123 However, activity of CYP1A2, which is responsible for hepatic elimination of many drugs, is decreased (33% in the first, 50% in the second, and 65% in the third trimester); activity of CYP2C19 is also decreased (50%).^5,6,78,123 CYP1A2 is also involved in clearance of caffeine so decreased activity may lead to slower clearance and enhance effects during pregnancy.^72,102

Activity of phase II enzymes is also altered during pregnancy, including some of the uridine 5′-diphosphatase glucuronosyltransferase (UGT) enzymes.^5,102,106 For example, UGT1A4 is increased 200% in the first and second trimesters and 300% in the third trimester; UGT2B7 is increased 50% to 200% by the third trimester.^6,123 Some extrahepatic enzymes, particularly cholinesterase, are also decreased, which may alter the woman’s response to neuromuscular agents.^28,36,131 For example, the decrease in pseudocholinesterase during pregnancy has been enough to impair breakdown of suxamethonium with subsequent prolonged paralysis after anesthesia in some women. The relative increase in hepatic metabolism and blood flow during pregnancy (as a consequence of the increased cardiac output), may increase clearance of polar drugs.³⁶ In general, slowly metabolized drugs that are cleared primarily by the liver tend to be cleared more slowly in pregnancy due to decreased enzymatic activity and the net decrease in liver blood flow. This may also increase the length of time potentially teratogenic intermediary metabolites remain in circulation.

Clearance and metabolism of drugs by the liver during pregnancy may also be influenced by the increases in steroid hormones that stimulate hepatic microsomal enzyme activity. For example, progesterone may induce enzyme activity for phenytoin clearance, whereas progesterone and estradiol alter hepatic elimination of caffeine and theophylline by competitive inhibition of microsomal oxidase.^36,81 Estrogens have cholinergic effects and may interfere with clearance of drugs such as rifampin that are excreted into the biliary system.⁸¹ Smoking and alcohol may also induce hepatic enzymes.

Renal drug excretion

Many drugs are excreted primarily by the kidneys. Thus the increased glomerular filtration rate (GFR) in pregnancy (see Chapter 11) alters renal excretion of drugs, especially water-soluble drugs such as penicillin G, digoxin, aminoglycosides, lithium, and pancuronium. These drugs are eliminated more rapidly, leading to lower and potentially subtherapeutic blood and tissue levels.^36,78,91 These effects are most prominent in late pregnancy.⁷² In many cases the changes are not clinically significant enough to require alteration in drug dose.³⁶ However, this is not always the case. For example, pregnant women with paroxysmal atrial tachycardia may experience an increased frequency of attacks when taking usual doses of digoxin. These women may require up to a 50% increase in their digoxin dose during pregnancy.⁸¹ In addition, shorter dosage intervals are recommended for nifedipine and labetalol due to a threefold increase in clearance in the pregnant woman.⁸¹ The half-life of atenolol, digoxin, and peripheral myorelaxants is shorter during pregnancy.¹⁰² Because lithium is eliminated entirely by GFR, the pregnant woman may require a higher dose of this drug, especially during the third trimester.⁸⁸ More rapid clearance and shorter half-lives are also seen with many penicillins, cephalosporins, aminoglycosides, and sulfonamides as a consequence of the changes in renal function during pregnancy.¹⁰² Morphine metabolites may be cleared more quickly in late pregnancy and may lead to a lowered analgesic effect.⁷²

Patterns of transfer kinetics

Three major patterns of transfer pharmacokinetics are seen: (1) complete transfer (drugs rapidly equilibrate between mother and fetus, with blood flow being the rate limiting step); (2) exceeding transfer (levels are higher in the fetus than in the mother); and (3) incomplete transfer (levels are higher in the mother than the fetus).⁹⁹ These patterns are illustrated in Figure 7-2. Examples of drugs with each pattern are listed in Table 7-3.

There is a great deal of variability even among drugs with similar pharmacokinetic characteristics. However, in general, complete transfer tends to be seen with drugs that have a high pKa and MW less than 600 daltons, whereas incomplete transfer is seen with drugs that have a high pKa and MW greater than 600 daltons. Strongly ionized drugs generally have incomplete transfer, although exceptions occur. For example, ampicillin and methicillin are strongly ionized but have lipophilic side groups, so they have a complete transfer pattern.^98,101 Valproate and salicylates are ionized at the normal (physiologic) pH level but rapidly cross the placenta.⁸¹

Factors influencing placental transfer

Most drugs cross the placenta by diffusion. Diffusion of a substance across the placenta can be expressed as follows:

< ?xml:namespace prefix = "mml" />Diffusion=Substance characteristics× Surface area× Concentration gradientDistance

Placental transfer is influenced by the following: (1) maternal and fetal drug handling; (2) surface area of the placenta; (3) diffusing distance between maternal and fetal blood; (4) physicochemical characteristics of the drug; (5) gradients (drug concentration, electropotential [normally 20 mV], and pH) between mother and fetus; (6) degree of binding of a substance to proteins in maternal and fetal circulations; (7) concentrations of binding proteins and protein binding gradients between mother and fetus; (8) permeability of the placental barrier (primarily the syncytiotrophoblast); (9) rates of maternal and fetal blood flow through the intervillous space and villi; and (10) placental influx and efflux transporters (Table 7-4).^{58,68,86,98,99,102,126}

Placental transporters.

Although many drugs cross the placenta by simple diffusion, some drugs use placental influx or efflux transporters. These transporters are located along the apical membrane of the microvillus brush border facing maternal blood in the intervillous space and on the syncytiotrophoblast basal membrane (facing the fetal connective tissue matrix and blood vessels in the villi) or fetal capillary epithelium to facilitate movement of nutrients and other physiologic substances across the placenta.^{44,58,91,98,102,106,120,126} Some drugs may also be transferred across the placenta by nutrient (influx) transporters, including glucose, carnitine, monoamine, and organic ion carriers.¹⁰² Nonphysiologic substances—some drugs, environmental pollutants, and toxins—if structurally similar to nutrients, may compete for nutrient transporters. The drugs that seem to be particularly able to use this method to cross the placenta include amphetamines, cocaine, cannabinoids, and nicotine and other substances from cigarettes.^44,129 By successfully competing with nutrients for these transporters, nutrient transfer is reduced and fetal growth and development altered. In addition, cephalosporins, ganciclovir, and corticosteroids cross by facilitated diffusion, probably by using carriers that normally transport dipeptides, hormones, and steroids.⁹⁸

The placenta also contains a variety of efflux transporters whose role is to remove steroids and other potentially toxic substances and thus protect the fetus.^{68,71,102,120,129,135} Originally most of the transporters were identified in studies of multidrug resistance in tumors as is reflected in some of their names. Examples of drug efflux transporters in the placenta include members of the APT-binding cassette (ABC) group such as multidrug-resistant gene protein (MRP) 1, commonly called P-glycoprotein (P-gp), MRP-2, MRP-3, and breast cancer resistance protein (BCRP).^{58,68,102,121,126,129,135} P-gp, MRP-2, and BCRP are located on the apical membrane of the syncytiotrophoblast cells facing maternal blood; MRP-1 and MRP-3 are on the basal or fetal side of the trophoblast (see Figure 7-3).^47,68,126 Efflux transporters are also found on the gut, lung, and blood brain barrier and help protect entry of substances into the body and brain. Efflux transporters are under hormonal regulation, for example, BCRP by estradiol, and progesterone and P-gp by glucocorticoids.¹²⁶ Inflammation and infection may alter regulation of these transporters.⁸⁹

Each transporter appears to have specific substrates for which they provide protection. For example, studies of P-gp suggest that it exports cations, steroids, cytotoxic drugs, some antibiotics, opioids, phenobarbital, erythromycin, phenytoin, verapamil, and other substances that enter the placenta back into maternal blood, thus reducing fetal exposure.^{20,58,102,135} BCRP is involved in efflux of flavinoids, zidovudine, cimetidine, glyburide, nitrofurantoin, and the food-borne chemical carcinogen PhiP.^58,68,102 MRP 1 and 3 prevent entry of organic anions and promote excretion and reduce entry of glutathione/glucuronide metabolites into the fetus.⁴⁷ Some transporters may have bidirectional flow which can allow xenobiotics to be transported across the placenta to the fetus.⁶⁸ Thus BCRP and P-gp cannot only decrease the amount of drug reaching the fetus but enhance removal of any drug reaching the fetal circulation.¹²⁹ A drug that is a P-gp or BCRP substrate would be preferred for treating a maternal disorder with minimal fetal drug exposure, whereas a drug that is not a P-gp or BCRP substrate would be preferred for fetal pharmacotherapy.¹²⁰

Deficiency of these transporter proteins increases the risk of teratogenesis from fetal drug and chemical exposure.^58,135 Gene polymorphisms for the ABC efflux transporters may increase or decrease placental transfer of these substances and thus alter fetal susceptibility to effects of maternal drugs.⁵⁸

Placental metabolism of drugs

The placenta has many enzyme systems, including various peptidases that can metabolize drugs, thus influencing transfer of specific substances from mother to fetus or fetus to mother.¹²⁰ Both phase I and phase II drug metabolizing enzymes are present.^106,129 Several isoforms of the CYP450 system (phase I reactions) are found in the placenta, although at levels about half of those seen in the liver. The primary CYP450 isoforms seen in the placenta are CYP1A1/1A2, although other isoforms, including CYP2E1, CYP3A4, CYP3A7, and CYP4B1, have also been reported, although with low activity.^{20,55,91,101,106,112,120}