Variation of Drug Kinetics in Pregnancy

Current Drug Metabolism, 2009, 10, 000-000 1

1389-2002/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Variation of Drug Kinetics in Pregnancy in Man

Petr Pávek*, Martina Ceckova and Frantisek Staud

Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, Hradec Kralove, 500 05 Czech Republic

Abstract: Significant changes in the physiological and biotransformation processes that govern pharmacokinetics occur during preg-

nancy. Consequently, the disposition of many medications is altered in gestation and the efficacy and toxicity of drugs used by pregnant women can be difficult to predict or can lead to serious side effects. Gastrointestinal absorption and bioavailability of drugs vary due to

changes in gastric secretion and small intestine motility. Various pregnancy-related hemodynamic changes such as an increase in cardiac output, blood volume, the volume of distribution (Vd), renal perfusion and glomerular filtration may affect drug disposition and elimina-

tion, and can cause increase or decrease in the terminal elimination half-life of drugs. Changes in maternal drug biotransformation activ-ity also contribute to alterations in pharmacokinetics of drugs taken in pregnancy. Therefore, pregnant women may require different dos-

ing regimens or their adjustment than both men and non-pregnant women. In addition, the prenatal pharmacotherapy is unique due to the presence of feto-placental unit. Considerations regarding transplacental pharmacokinetics and safety for the developing fetus are thus es-

sential aspects of medication in pregnancy.

The aim of this review is to summarize major physiological and biotransformation changes associated with pregnancy that affect pharma-cokinetics in pregnant women. In addition, we point out the most important examples of altered kinetics of drugs administered in preg-

nancy with mechanistic explanation of the phenomena based on maternal adaptation in pregnancy.

Keywords: Pharmacokinetics, metabolism, placenta, pregnancy, ADME, pharmacotherapy, fetus, physiological alternation.

1. INTRODUCTION

Increasing number of pregnant women require continuous or occasional treatment during gestation to treat serious diseases such as asthma, diabetes mellitus, epilepsy, migraine, hypertension etc. In addition, new reasons for medication can appear or some dis-eases can be exacerbated during pregnancy. Use of herbal and over-the-counter medications is also widely common among pregnant women. Pharmacotherapy in pregnancy represents a significant challenge in terms of effectively treating the maternal illness, whilst simultaneously minimizing side effect for the fetus. Maternal risks associated with drug withdrawal or dose reduction may predispose the unborn child to more harm than drug side effects themselves, which usually justifies continued pharmacotherapy even for drugs with known teratogenic potential such as antiepileptics [1]. Clini-cians therefore often weigh the risks of fetal drug exposure and teratogenicity against risks to the fetus due to untreated maternal diseases.

Physiological adaptations during pregnancy are essential to meet the demands of both mother and the developing fetus. Signifi-cant physiological alterations occur in the renal, gastrointestinal, and cardiovascular systems and in the liver in gestation, which af-fect basic pharmacokinetic processes: drug absorption, distribution, metabolism and excretion. The disposition of many medications is thus altered in pregnant women [2]. This urges us to understand the alternations during pregnancy since more than 96% of pregnant women are prescribed at least one medication [3].

In addition, the prenatal pharmacotherapy is unique due to the presence of feto-placental unit. Although both placental and fetal hepatic biotransformation capacities are low and do not substan-tially contribute to overall maternal drug clearance, the placenta partially controls fetal exposure to some drugs. The placenta con-tains metabolizing enzymes, which can convert a drug into an inac-tive metabolite to prevent fetal exposure or activates xenobiotics to more dangerous toxins [4]. Transplacental passage of drugs and potential fetotoxicity are the major concerns in the pharmacother-apy of the pregnant patient.

*Address correspondence to this author at the Department of Pharmacology

and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles Univer-sity in Prague, Heyrovskeho 1203, Hradec Kralove, 500 05 Czech Republic;

E-mail: ????????????????????????

2. ABSORPTION

2.1. Gastrointestinal Absorption

According to earlier reports, gastric emptying time is signifi-cantly prolonged during pregnancy [5]; however, later reports ques-tioned the notion [6,7]. Delay in gastric emptying is most pro-nounced shortly before term, further intensified by general anesthe-sia [8]. Intestinal passage is prolonged by 30-40% in the second and third trimesters, compared to first trimester and almost two-times longer compared to post-partum [9]. This prolonged passage can enhance absorption of slowly absorbed drugs during pregnancy, while well absorbed drugs may show delay in absorption.

Bioavailability of iron and calcium is enhanced after oral ad-ministration in pregnant women [10,11]. Decreased absorption of some drugs in pregnancy can cause sudden elevation of plasma concentrations post partum after per os administration of the same dose. Furthermore, frequent vomiting during pregnancy has a pro-found effect on drug absorption.

Gastric secretion of pregnant women shows a different biological activity compared to non-pregnant [12] and hydrochloric acid se-cretion is reduced in first and second trimester to less than 40%. In addition, activity of peptidases is decreased [13]. On the contrary, secretion of mucus is elevated. These changes result in higher pH in the stomach, which affects absorption of certain compounds, mainly of weak acids.

2.2. Pulmonary Absorption

The minute ventilation is increased by 7-8 weeks of gestation, but with no change in breathing frequency [14]. The hyperventila-tion in pregnancy is linked with increase in respiratory volume by 40% and decrease in residual volume of the lung by 20% [15]. Ele-vated cardiac output results in higher blood perfusion of the pulmo-nary alveoli. This causes faster equilibration of volatile compounds between alveolar compartment and blood and causes higher pulmo-nary absorption of anesthetics, bronchodilators, pollutants, cigarette smoke and other drugs.

2.3. Parenteral Absorption

Vasodilatation and higher cardiac output cause elevated blood perfusion at the periphery. Therefore, faster absorption occurs after transdermal, intranasal, intravaginal, epidural and subcutaneous

2 Current Drug Metabolism, 2009, Vol. 10, No. 5 Pávek et al.

administration [16]. Lower plasma concentrations reported after subcutaneous administration of heparin in pregnancy may be due to the larger volume of distribution [17]. Plasma concentrations after epidural administration may even be comparable to those after in-travenous injection, e.g. in case of pethidine [18]. Towards the end of pregnancy, blood perfusion in legs decreases which may cause decline in drug absorption after intramuscular administration [19].

3. DISTRIBUTION

There are several factors that affect drug distribution in preg-nancy, mainly higher volume of total body fluid and larger volume of distribution, elevated amount of fat, higher cardiac output and faster heart rate.

3.1. Blood

Reduced peripheral vascular resistance in the early pregnancy (by 6 weeks) activates compensation mechanisms which contribute to a 14% increase in plasma volume by 12 weeks [110] and to ap-proximately 50% increase in the third trimester of pregnancy with considerable interindividual variability [21-23]. Change in plasma volume also depends on number and size of fetuses; mothers with more than one fetus show more pronounced increase in plasma volume [23] while mothers with small, slowly developing fetus undergo lower plasma volume increase [24]. The volume of eryth-rocytes increases by 18% at the end of pregnancy (see Table 1). Disproportion in plasma volume vs. concentration of red blood cells leads to decrease in hemoglobin concentration to 110g/l. Changes in plasma protein concentrations are reviewed in the chapter 3.5.

The physiological changes in pregnancy produce a hypercoagu-lable state that increases the risk of venous thromboembolism. The antithrombotic agents available for the prevention and treatment of venous thromboembolism during pregnancy include unfractionated heparin (UFH), low-molecular-weight heparin (LMWH) and aspi-

rin [25]. Blomback and coworkers reported the pharmacokinetic profile of the LMWH dalteparin by measuring plasma anti-Xa activity in women in the third trimester [26]. The maximum con-

centration for anti-Xa activity (Cmax), the time at which Cmax ap-pears (tmax), and the area under the curve (AUC0-24) were reduced in the pregnant women. The differences are likely caused by the larger plasma volume, lower protein concentration and increased renal clearance associated with pregnancy [25]. Casale and coworkers have also shown that the AUC of subcutaneously administered enoxaparin is reduced during pregnancy compared with the same women after delivery, which is likely a consequence of increased renal clearance of enoxaparin during pregnancy [27]. In other stud-ies with LMWH tinzaparin and dalteparin, anti-Xa levels were also found to be reduced in pregnancy [25,28,29].

Peak concentrations (Cmax) of mefloquine, an antimalarial drug, were significantly lower in the pregnant patients and the total ap-parent volume of distribution (Vd/F) was larger, consistent with an expanded circulating blood volume and increased tissue binding in pregnancy [30]. Oral blood clearance (CL/F) of another antimalarial drugs chloroquine, atovaquone and proguanil were reported to increase and plasma levels significantly decrease during the preg-nancy [31-33].

3.2. Body Fluid

Changes in total body fluid are summarized in Table 2. It shows that the volume of body fluid can increase by about 6-8 liters; 80% of this is distributed in extracellular and 20% in intracellular spaces. 60% of this fluid is present in the placenta, fetus, amniotic fluid and uterus. Increase in body fluid is caused by natrium retention, de-crease in oncotic pressure and increase in capillary hydrostatic pres-sure. Considerable increase in total body fluid is often connected with edemas in mothers. Generalized edema causes an average increase of 5 liters of extracellular fluid.

It is obvious, that changes in total body fluid and plasma vol-ume during pregnancy have substantial effect on distribution and elimination of drugs, especially polar, water soluble ones. Moreo-ver, the increased volume of distribution causes the decrease in peak serum concentrations of hydrophilic drugs.

Table 1. Changes in Plasma Volume During Pregnancy (mL)

Non-pregnant Week 20 Week 30 Week 40

Plasma volume 2600 3150 3750 3600

Erythrocyte volume 1400 1450 1550 1650

Total blood volume 4000 4600 5250 5250

Based on [104].

Table 2. Body fluid Increases in Pregnant Women (Numbers Represents Weight of Water in Tissues in Grams)

Week 20. 30. 40.

Fetus 264 1185 2412

Placenta 153 366 540

Amniotic fluid 346 742 792

Uterus 264 495 800

Mammary gland 135 270 304

Blood 538 1156 1083

Extravascular extracellular water

- woman without edema 30 80 1680

- woman with generalized edema 500 1526 4897

Total increase in body fluid in pregnant women without edema 1740 4300 7500

Total increase in body fluid in pregnant women with generalized edema 2230 5740 10830

Based on [105]

The Variation of Drug Kinetics in Pregnancy in Man Current Drug Metabolism, 2009, Vol. 10, No. 5 3

3.3. Body Fat

The average gain in body fat during pregnancy, mainly in the first two trimesters, is about 3 to 4 kg. This fat preferentially cumu-lates in subcutaneous depots, in which lipid soluble xenobiotics accumulate. In the third trimester, however, the fat is metabolized and higher plasma concentrations of lipoproteins, glycerol [34] and fatty acids occur [35]. Increased amount of fatty acids may compete for plasma protein binding with drugs resulting in elevated free drug concentration in plasma [36]. During 6 months post partum, most of this fat is metabolized, which leads to release of accumu-lated lipophilic drugs.

3.4. Circulatory System

Cardiac output starts to increase by 5-6 weeks of pregnancy and further continues to increase by 30-40% during the second trimes-ter, after which the cardiac output plateaus [21,37,38]. With in-creasing contractions at term, cardiac output further raises by 50-100% [20,22]. Heart rate increases by 10-15% in the first trimester with no additional increase thereafter [38,39]. It is supposed, that increased cardiac output is distributed mainly to the uterus and kidneys; blood perfusion rises by 500 mL/min in these organs. In addition, increased blood perfusion was reported in the lung, mam-mary glands, splanchnic areas and skin. At the end of pregnancy, blood circulation in the uterus reaches 500-600 mL/min, 80% of which perfuse the placenta [40].

Contractions of uterus may decrease or even block access of blood to the placental villi; therefore, when given at the onset of contractions, drug transfer across the placenta is reduced [41].

Hepatic blood flow also increases during pregnancy up to 160% of non-pregnant flow; however, the hepatic arterial blood flow re-mains unchanged during pregnancy. This is due to the increase in the portal venous return [109]. Thus, the first-past hepatic clearance of high extraction ration drugs, whose hepatic clearance is domi-nantly dependent on the liver perfusion, should be affected in preg-nancy. However, this is not true for all high extraction ratio drugs such as morphine, propranolol and midazolam, since also other kinetics factors affected in gestation are involved in controlling distribution and elimination of the drugs [3].

3.5. Plasma Protein Binding

Plasma protein concentration and drug binding capacity are altered in the mother and fetus as pregnancy advances. The phar-macological efficacy and toxicity of xenobiotics are also linked with the concentration of free compound in both the mother and fetus and only free fractions of drugs in blood can cross the placen-tal barrier and reach the fetus or can be eliminated from the fetus.

Both maternal and fetal albumin and -1 acid glycoprotein con-centrations change during pregnancy, which has important implica-tions for disposition of both weak bases and acids and affects the equilibration of some compounds between fetus and mother. Moreover, total blood protein concentration decreases at term by 12% (Table 3). Maternal serum albumin concentrations decrease

during the course of pregnancy, which is due to a dilutional effect caused by the increase in plasma volume (Table 3). Fetal serum albumin is much lower in early gestation (12-15 weeks), ranging from 7.5 to 16 g/l and increases to reach the same concentration as in the mother at 30 weeks. After 35 weeks the fetal concentration exceeds the maternal by 20%, but still does not reach normal adult levels of albumin. The mean fetal/maternal serum concentration ratio of albumin increases from early pregnancy to term: 0.38 at 12-15 weeks; 0.66 at 16-25 weeks; 0.97 at 26-35 weeks; and 1.2 after 35 weeks of gestation [42].

Maternal serum alpha 1-acid glycoprotein concentrations range between 0.38 and 1.05 g/L. Fetal serum concentration of alpha 1-acid glycoprotein is very low before 16 weeks of gestation, then it increases, but never attains the maternal values. Near term a fe-tal/maternal serum concentration ratio of 0.37 is reached for alpha 1-acid glycoprotein [42].

In addition to albumin and alpha 1-acid glycoprotein, human -fetoprotein has also been shown to bind some marker compounds for albumin binding sites (such as warfarin, phenylbutazone, L-tryptophan) [43].

Pregnancy-related hypoalbuminemia, leading to decreased plasma protein binding, results in increased free drug fraction. However, as more free drug is available for either hepatic biotrans-formation or renal excretion, the overall (net) effect of elevated free drug plasma concentration is minimal [44]. Although the absolute magnitude of a free drug increase might be small, the relative change in free fraction may be significant in terms of augmentation of its pharmacodynamic effect.

Total plasma concentration of old-generation antiepileptics as well as their free drug concentration decline in pregnancy [45]. With respect to individual drugs, the decreases in the total plasma concentration and free drug concentration in the third trimester are for phenytoin 55-61% (18-31% for free drug), for carbamazepine 0-42% (0-28% for free drug), for total phenobarbital 50-55%, for total primidone 55%, for valproic acid 50% (minor changes or slight increase for free valproic acid concentration reported) [45-48]. Although both total and free plasma concentrations decrease, free drug fraction (ratio of free to total plasma concentration) might increase. Significant increase in concentration of free bupivacaine throughout gestation has been reported [49]. Decreased binding to plasma proteins during pregnancy have been also reported for lido-

cain, diazepam and theophylline [50].

In addition, it has been shown in several studies that changes in protein concentrations and pH affect the placental transfer of drugs using the dual perfused single cotyledon human placental model (see review by [4]). pH of fetal blood is slightly lower (about 7.3) than maternal blood. Consequently, drugs that are weak bases are more ionized in the fetal circulation than in maternal circulation and may accumulate in the fetus (ion trapping phenomenon). This effect may be intensified in the presence of fetal acidosis (e.g., during labor) [51].

Table 3. Changes of Plasma Composition in Pregnancy

Month of gestation 3 4 5 6 7 8 9

Plasma volume (liters) 2.63 2.81 3.06 3.39 3.65 3.75 3.76

Total plasma protein (g/L) 71 67 67 66 65 64 63

Albumin (g/L) 44 41 39 39 36 34 32

-1 acid glycoprotein 0.72 0.63 0.56 0.54 0.57 0.60 0.50

Total globulins (g/L) 25.7 26.2 26.5 28.1 27.6 29.1 30.8

Lipids (g/L) 6.5 6.9 7.5 7.4 9.0 9.6 10.2

Modified from the report [50]


3.6. Transplacental Passage of Drugs

Pharmacokinetics in pregnant women is unique also due to the presence of feto-placental unit, a special compartment formed by the developing fetus and placenta. The human placenta is of the haemochorial type, in which the fetal tissue is in direct contact with maternal blood. Placenta brings the blood circulations of mother and her fetus into close apposition, while maintaining separation of the two blood systems. Trophoblast covering each placental villous tree represents the rate-limiting barrier for transplacental transfer of most substances.

Generally, any chemical substance administered to mother is able to permeate, to some degree, across the placenta [4,51-53]. Unfractionated heparin and low-molecular-weight heparins in the treatment of venous thromboembolism are exceptions, which due to larger molecule (higher than 4000 Da), do not cross the placental barrier [25]. Similarly, insulin and its analogs, which have rela-tively high molecular weight, do not cross the placenta. Therefore, insulin is the treatment of choice in women with gestational diabe-tes [54].

Non-ionized and lipophilic molecules with molecular weight up to 600 Da cross the placenta via passive diffusion, unless they are metabolized or altered during passage. Drugs and xenobiotics that are structurally related to endogenous compounds can be addition-ally recognized as substrates of nutrient transporters like mono-amine, carnitine, nucleoside and organic ion transporters (reviewed in [55-57]). Transcytotic processes also help to supply the nutrient and immunoglobulin transport to the fetus during gestation [58], but it seems to be of minor importance for transplacental transfer of commonly used drugs [59].

3.7. Drug Efflux Transporters

In recent years, disclosure of ABC drug efflux transporters in the placental barrier has brought new important insights into the field of transplacental pharmacokinetics. The group of ATP-dependent membrane pumps (ABC transporters) includes P-glycoprotein (P-gp, MDR1, encoded by ABCB1 gene), multidrug resistance-associated proteins (MRPs encoded by ABCC1-6 and ABCC10-12) and the breast cancer resistance protein (BCRP, en-coded by ABCG2 gene). P-gp is the first discovered and so far the best characterized ABC drug efflux transporter expressed in the placental trophoblast layer [60]. It is able to pump an extremely wide variety of chemically and structurally diverse compounds including cytotoxic drugs, HIV protease inhibitors, antibiotics, opioids, antiemetics and many other xenobiotics (reviewed in [61,62]) across the placenta in feto-maternal direction and provides thereby protection to the developing fetus. As a clinical conse-quence, administration of P-gp substrates could be favored in pharmacotherapy of pregnant women to reduce fetal drug exposure, toxicity and risk of malformations. On the other hand, drugs that are not recognized as P-gp substrates could be preferred in cases where fetus is the target of pharmacotherapy. Placental P-gp also presents a risk of drug-drug interactions; administration of drugs acting as P-gp inhibitors can unfavorably increase exposition of fetus to P-gp substrates [60].

High expression of BCRP in the trophoblast layer of placental chorionic villi has been recently discovered [63,64]. Current data strongly suggest that like P-gp, placental BCRP plays an important role in protection of the fetus against the potential toxicity of drugs, xenobiotics and metabolites [65]. There is an overlap in substrate specificity between P-gp and BCRP [66]; however, BCRP can ex-clusively transport many substances, e.g. nitrofurantoin, glyburide or food-born chemical carcinogen PhiP and influence their trans-placental transfer [4,67,68]. Interaction of glyburide with BCRP well explains minimal placental transfer of glyburide, the drug rec-ommended for the treatment of diabetes mellitus in pregnant women [54,69]. Several MRP transporters have also been detected in human placenta [70-74]; however, their role in the distribution of

drugs and/or their metabolites between mother and fetus is still under investigation.

4. BIOTRANSFORMATION

4.1. Liver Metabolism in Pregnant Women

The metabolic activities of CYP3A4, CYP2D6, CYP2A6 and CYP2C9 and uridine 5´-diphosphate glucuronosyltransferase (UGT) isoenzymes (i.e. UGT1A1, UGT1A4 and UGT2B7) are increased during pregnancy, which may need dosage regiment ad-justment for optimal pharmacotherapy [3,75]. Importantly, in-creased biotransformation of xenobiotics, toxins and compounds with mutagenic potential causes rapid clearance from maternal circulation, which decreases the amount of the compound available for the transplacental passage. Thus, maternal hepatic biotransfor-mation determines (to some extent) fetal exposure of xenobiotics. In contrast, CYP1A2 and CYP2C19 activities are decreased during pregnancy, suggesting that dosage reductions may be necessary to minimize potential toxicity of their substrates [3,75].

CYP1A2: CYP1A2 enzymatic activity significantly fall throughout pregnancy by 33% in the first trimmest and up to 65 % in the third trimester [76,77]. Consistently, caffeine, a probe sub-strate of CYP1A2 activity, is substantially less metabolized during pregnancy [3]. In accordance, clearance of another CYP1A2 drug substrate theophylline, is decreased during the third trimester of pregnancy [78].

CYP2A6: Enzymatic activity of CYP2A6 significantly in-creases in the second and third trimesters. Accordingly, clearance of both nicotine and cotinin, substrates of CYP2A6, augment in the pregnancy [3].

CYP2C9 and CYP2C19: Metabolizing activity of CYP2C9 also increase during pregnancy [3]. Phenytoin, a well-known substrate of CYP2C9 4´-hydroxylation, display increased clearance through-out the pregnancy [45,48]. In contract, CYP2C19 activity is de-creased during pregnancy [3]. Consistently, bioconversion of nelfi-

navir, a protease inhibitor activated by CYP2C19 to its active me-tabolite hydroxy-t-butylamidenelfinavir (M8), is decreased in the third trimester likely due to the reduction in CYP2C19 activity [79].

CYP2D6: Enzymatic activity of CYP2D6 is up-regulated dur-ing pregnancy by 26% in the first trimester and by 48% in the third trimester [76]. Increased demethylation of fluoxetine in pregnancy was reported and authors connected the phenomenon with the ges-tational induction of CYP2D6 [80].

CYP3A4: The most important enzyme of the cytochrome P450 family, CYP3A4 is also induced during all stages of the pregnancy and both hepatic and/or intestinal CYP3A activity is increased 2-3 fold in late pregnancy compared with postpartum [78, 111]. Consis-tently, metabolism of methadone, nifedipine and indinavir, sub-strates of CYP3A4, increase in pregnancy [81-82].

Antiepileptic drug lamotrigine is metabolized mainly by phase II enzymes uridine diphosphate glucuronosyltransferases (UGTs). A significant increase in lamotrigine clearance during pregnancy is attributed to gestation-related up-regulation of UGT1A4 enzyme, the major biotransformation enzyme of the drug [45,83]. In con-trast, N-acetyltransferase 2 (NAT2) activity of another phase II enzyme was found to decrease in the pregnancy [77].

Important issue, which remains to address, is xenobiotic- or hormonal-mediated transcriptional regulation of cytochrome P450 enzymes, phase II conjugation enzymes and drug transporters through nuclear receptors in pregnancy [112]. For instance, CYP3A4 expression is regulated by a number of nuclear receptors, including the pregnane X receptor (PXR), constitutive androstane receptor (CAR), the glucocorticoid receptor (GR), hepatocyte nu-clear factor 4 (HNF4 ), farnesoid X receptor (FXR), and the vita-min D receptor (VDR) [113]. CYP2A6, CYP2C9, CYP2C19 as well as glutathione S-transferase SULT2A1 are regulated by gluco-


corticoids and GR [112, 114,115]. Vitamin D receptor control in-ducible transativation of CYPs such as CYP3A4 and CYP2C9. CYP1A2 and CYP1A1 are under transcriptional control of Arylhy-drocarbon receptor (AhR), which binds both xenobiotics and endo-biotics [116]. Cigarette smoke contains a large number of AhR ligands such as polychlorinated dibenzo p-dioxins, polychlorinated dibenzofurans, coplanar polychlorinated biphenyls and polycyclic aromatic hydrocarbons (PAHs). Importantly, up-regulated placental CYP1A1 is involved in the bioactivation of carcinogenic and promutagenic polycyclic aromatic hydrocarbons to DNA-reactive species forming DNA adducts both in the placenta and fetal tissues. Consequently, cigarette smoking during pregnancy affects the health of both mothers and children, causes higher risk of spontane-ous abortion, low birth weight, perinatal mortality, malformation of infants, especially oral cleft, and postnatal effects including sudden infant death and respiratory disorders [117].

4.2. Placental Metabolism

The extent to which drugs cross the placenta is also thought to be controlled by activities of placental phase I and II drug-metabolizing enzymes. Although the attractive idea that the pla-centa acts as a “metabolic barrier” to drugs is accepted, it seems that for most drugs placental drug biotransformation is of relatively minor importance and is not significant factor in limiting the extent of fetal exposure to xenobiotics [51]. On the other hand, some xenobiotics with procancerogenic or promutagenic potential can be activated by placental biotransformation enzymes to active toxins (see review [108]).

The placental trophoblast expresses several enzymes of cyto-chrome P450 family (CYPs) at mRNA level, although only few of them have significant enzymatic activity (Table 4). More CYP en-zymes are expressed in the first trimester of pregnancy in compari-son with full-term placenta [51,84,85]. In the second and third tri-mesters activities of xenobiotic metabolizing CYPs decline [85]. CYP1A1 is the only placental xenobiotic metabolizing enzyme for which enzymatic activity and inducibility have been convincingly demonstrated in the placental trophoblast throughout pregnancy. Consistently, AhR and ARNT nuclear receptors regulating ligand-inducible expression of placental CYP1A1 are abundant in the pla-cental trophoblast [86].

Recently, several studies unravel the mechanism, how envi-ronmental toxins interfere through AhR pathway with estradiol receptor signaling and function [118]. Similarly, activated AhR was shown to affect signaling of GR receptor and vice versa [119]. The links between signaling pathways may explain detrimental effect of environmental pollutants and cigarette smoke toxins to human re-production.

Conjugating-enzyme activities reported in the placenta are glu-tathione S-transferase (GST), N-acetyltransferase, sulfotransferase (SULT) and uridine 5 -diphosphate glucuronyltransferase (see re-views [4,51]). UGTs are present in the placenta throughout the entire gestation and probably play a major role in placental biotransformation of xenobiotics [4,51].

The plasma clearance of betamethasone phosphate and its apparent volume of distribution are higher in pregnant women than found for non-pregnant subjects, but its half-life was unchanged

Table 4. Cytochrome P450 (CYP) Expression and Activity in First Trimester and Term Human Placenta

CYP isoenzyme First trimester Term

CYP1A1 +abcd +abcd

CYP1A2 +a –a

CYP1B1 +ae +ae

CYP2A6 +/–a +/–a

CYP2A13 –a –a

CYP2B6 +/–a +/–a

CYP2C8 –af –af

CYP2C9 +af –af

CYP2C19 +af –af

CYP2D6 ++a, –c –a, –c

CYP2E1 +ab, –/+c +ab, –/+c

CYP2F1 +/-a +/-a

CYP2J2 n.d. ++a

CYP2R1 n.d. +a

CYP2S1 n.d +a

CYP3A4 +ab +a,–/+b,–c

CYP3A5 +ab +a,–/+b

CYP3A7 +ab –/+ab

CYP3A43 –a –a

Based on tables in [51, 84-85, 106-108].

++ = high expression; + = low expression; - = undetectable expression; +/- = controversial expression or reports; n.d. – not determined a mRNA expression. b immunoreactivity of protein. c enzymatic ativity. d highly inducible in the placenta. e non-inducible. f total CYP2C expression reported in the first trimmest [85]


[87]. Authors of the study speculated that the increase in be-tamethasone clearance is due to increased metabolism possibly by the placental/fetal unit. Consistently with the assumption, women with twin gestations have higher clearance of betamethasone than singleton gestation [88].

4.3. Fetal Metabolism

The fetal liver is formed by the end of the first trimester. The fetal hepatic circulation differs substantially from that of the adult. In the fetus, an extra input vessel, the umbilical vein, exists and there is shunting of 30-70% of hepatic blood flow via the ductus venosus (see review [89]).

The ability of the fetus to metabolize xenobiotics from early gestation is now well established, although enzymatic activities of major CYPs are much lower in early gestation in comparison with adult liver (normalized to mg of liver proteins)[90]. Because me-tabolites are generally more water-soluble than parent drugs, they diffuse less easily across biological membranes. Consequently, when formed within the fetus, metabolites will tend to be trapped and accumulate in the fetal compartment.

Of the enzymes of cytochrome P450 family, CYP3A7 accounts for up to 50% of total fetal hepatic cytochrome P450 content and its protein level is about 10 times higher in comparison with other CYPs [91]. Expression of the enzyme is the highest in the 20

th week

of gestation and decreases dramatically after birth. CYP1A1 and CYP2D6 proteins and enzymatic activities have also been detected in human fetal liver, although contradictory reports exist [89]. CYP1A1 is likely expressed throughout pregnancy, even though only expression in the first trimester (during organogenesis) has been well documented. CYP2C19 protein and catalytic activity is expressed significantly by 8 weeks of gestation and the expression exceeds the expression of CYP2C9 (12-15% versus 1-2% of adult liver expression, respectively) [92]. CYP3A5 and CYP2C8 mRNAs have also been detected in the fetal liver; other CYPs such as CYP1A2, CYP2F1, CYP2B6 are not detectable [93]. Controversial reports exist whether CYP2E1 is expressed in the fetal liver in first trimester [89,91].

Expression and enzymatic activity of additional phase I and II enzymes have been documented in the fetal liver such as epoxide hydrolases, glutathione S-transferases, sulfotransferases [89,90]. Significant activity of sulfation enzymes to numerous endogenous hormones (dehydroepiandrosterone, cortisol, estrogen, testosterone etc.) as well as to drugs (ritodrine, paracetamol) have been re-ported [89,94]. Sulfotransferase activity develops early in the hu-man fetal liver. In mid-gestation they may exceed activity of adult liver although remarkable interindividual variability exists [94]. In contrary, limited activity of glucuronidation enzymes (UDP-glucuronosyl-transferases) is present in the human fetal liver [89].

Fetal hepatic drug conjugation enzymes form more water solu-ble conjugates and thus may prolong fetal exposure to the metabo-lites. The conjugates if excreted in fetal urine can be recycled in the fetus via amniotic fluid and fetal swallowing through the intestinal tract. This recirculation prolongs elimination of hydrophilic sub-stances and metabolites from the fetus, since the conjugates hardly cross the placenta back to the mother to be eliminated by maternal elimination.

5. EXRETION

5.1. Renal Excretion

Glomerular filtration increases by up to 80% at the beginning of gestation due to increase in renal blood flow, decreased renal vascu-lar resistance and larger cardiac output [22,37,95-97]. On the other hand, glomerular filtration rate decreases during the last 3 weeks of pregnancy [75]. Increased free fraction of a drug in plasma during pregnancy also contributes to the higher glomerular filtration. Both kidney perfusion and glomerular filtration rate show postural de-

pendence. Increased clearance of hydrophilic compounds is not as marked if pregnant woman is lying [98].

Consistently with the increased glomerular filtration in preg-nancy, renal excretion of lithium, a drug eliminated entirely un-changed by the glomerular filtration, increases dramatically during the third trimester, often necessitating concomitant increase of the maternal dose [1]. In consequence of pregnancy-related elevated glomerular filtration of hydrophilic drugs eliminated preferentially by the kidney, such as atenolol, digoxin, periphery myorelaxants and others, their half-lives are significantly shorter in pregnant women [3, 44]. Among the hydrophilic antibacterial agents, it has been reported that numerous penicillines, cephalosporines, amino-

glycosides, and sulphonamides show faster clearance, shorter bio-logical half-lives and larger distribution volumes after parenteral administration [44, 99-102]. Phenytoin is known to show saturation kinetics of elimination; Km of phenytoin elimination is almost doubled during pregnancy [103].

6. DISCUSSION

Substantial changes in the physiological and biotransformation processes that control pharmacokinetics occur during all stages of pregnancy and absorption, distribution, metabolism and excretion of most medications is altered in gestation. Therefore the efficacy and toxicity of drugs used by pregnant women can be difficult to predict or can lead to serious side effects.

Changes in maternal hepatic biotransformation activity, which are mostly hormone-dependent, also contribute to alterations in the pharmacokinetics in pregnant women.

Knowledge of the pregnancy-related physiological alterations can improve our ability to predict the impact of pregnancy on pharmacotherapy and improve clinical care when clinical data re-garding medication in pregnancy are lacking or limited. Although the number of studies being conducted with individual drugs is increasing, the clear guidelines for adjusting drug doses during pregnancy are often lacking [2]. Moreover, the pharmacokinetics data from studies in pregnant women should be interpreted with caution, since high interindividual variability is usually reported (caused by environmental, genetic and lifestyle conditions) and the population size of most studies published in literature is small. More extensive clinical studies in pregnancy are complicated by ethical and safety reasons for both mother and fetus. Even more challenging is the fact that the physiological changes and enzymatic activities of metabolizing enzymes summarized in the review are dynamic throughout gestation, implying specific dosage adjust-ments of commonly used drugs during each trimester of pregnancy. Finally, co-medication with metabolizing enzyme-inducing or in-hibiting drugs during pregnancy was not always systematically studied and can lead to serious drug-drug interaction with different character and intensity in comparison to non-pregnant patients [2].

Pharmacokinetic modeling can be applied to estimate pharma-cokinetics of a drug in gestation considering the changes in Vd, clearance, and in the terminal elimination half-life. Therapeutic drug monitoring has been recommended to monitor the disposition of many drugs administered in the pregnancy [1,2,25]. However, further evaluation is required to clarify the clinical impact of de-creased total as well as free drug plasma concentration during preg-nancy for the pharmacodynamic effect in pregnant women and the significance of the change for drug distribution and elimination.

Pharmacotherapy in pregnancy is also connected with consid-eration of fetal toxicity and adverse fetal reactions. Since most of drugs administered to pregnant women cross the placenta and reach significant levels in fetal circulation, transplacental transport of drugs and their metabolic profile in the fetus should also be taken into account before application of a drug to pregnant women. Re-cent advances in our understanding of mechanisms of transplacental pharmacokinetics and the ontogeny of drug-metabolizing capacity


and its regulation in fetus should help us to avoid a potential harm-ful effect of pharmacotherapy to developing fetus.

In conclusion, by evaluating and considering physiological, biotransformation and hemodynamic alternations during pregnancy, we can predict the effect of pregnancy on pharmacokinetics of some clinically used drugs; optimize drug therapy of pregnant women as well as to avoid serious injury of the fetus. However, more clinical data are needed to comprehensively elucidate and distinguish the effects of various factors altered in pregnancy on the pharmacokinetics of an individual drug to increase therapeutic benefit while minimizing side effect for both the mother and the fetus.

ACKNOWLEDGEMENT

This manuscript was supported by the Czech Scientific Founda-tion (GACR 303/07/0128) and by the Internal Grant Agency of the Ministry of Health (NR/9209-3 (both to P.P.).

LIST OF ABBREVIATIONS

AhR = Arylhydrocarbon receptor

ARNT = AhR nuclear translocator

AUC = The area under the curve

BCRP = Breast cancer resistance protein (ABCG2 gene product)

CL/F = Oral blood clearance

Cmax = Maximum concentration

CYP = Cytochrom P-450

GST = Glutathione S-transferase

Km = The Michaelis-Menten constant

LMWH = Low-molecular-weight heparin

NAT = N-acetyltransferase

ABC transporters = ATP-binding cassette transporters

P-gp = P-glycoprotein

tmax = The time at which Cmax appears

UGT = Uridine 5´-diphosphate glucuronosyltransferase enzyme

UFH = Unfractionated heparin

Vd = The volume of distribution

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Received: June 17, 2009 Revised: June 29, 2009 Accepted: July 01, 2009

Variation of Drug Kinetics in Pregnancy

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