Observational studies have documented that women take a variety of medications during pregnancy. It is well known that pregnancy can induce changes in the plasma concentrations of some drugs. The use of mechanistic-based approaches to drug interactions has significantly increased our ability to predict clinically significant drug interactions and improve clinical care. This same method can also be used to improve our understanding regarding the effect of pregnancy on pharmacokinetics of drugs. Limited studies suggest bioavailability of drugs is not altered during pregnancy. Increased plasma volume and protein binding changes can alter the apparent volume of distribution (Vd) of drugs. Through changes in Vd and clearance, pregnancy can cause increases or decreases in the terminal elimination half-life of drugs. Depending on whether a drug is excreted unchanged by the kidneys or which metabolic isoenzyme is involved in the metabolism of a drug can determine whether or not a change in dosage is needed during pregnancy. The renal excretion of unchanged drugs is increased during pregnancy. The metabolism of drugs catalysed by select cytochrome P450 (CYP) isoenzymes (i.e. CYP3A4, CYP2D6 and CYP2C9) and uridine diphosphate glucuronosyltransferase (UGT) isoenzymes (i.e. UGT1A4 and UGT2B7) are increased during pregnancy. Dosages of drugs predominantly metabolised by these isoenzymes or excreted by the kidneys unchanged may need to be increased during pregnancy in order to avoid loss of efficacy. In contrast, CYP1A2 and CYP2C19 activity is decreased during pregnancy, suggesting that dosage reductions may be needed to minimise potential toxicity of their substrates. There are limitations to the available data. This analysis is based primarily on observational studies, many including small numbers of women. For some isoenzymes, the effect of pregnancy on only one drug has been evaluated. The full-time course of pharmacokinetic changes during pregnancy is often not studied. The effect of pregnancy on transport proteins is unknown. Drugs eliminated by non-CYP or non-UGT pathways or multiple pathways will need to be evaluated individually. In conclusion, by evaluating the pharmacokinetic data of a variety of drugs during pregnancy and using a mechanistic-based approach, we can start to predict the effect of pregnancy for a large number of clinically used drugs. However, because of the limitations, more clinical, evidence-based studies are needed to fully elucidate the effects of pregnancy on the pharmacokinetics of drugs.

Pregnancy-induced changes in pharmacokinetics: a mechanistic-based approach.

There are a number of examples of sex differences in drug pharmacokinetics and pharmacodynamics. Recent advances in the characterisation of specific isozymes involved in drug metabolism now allow for the preliminary identification of enzyme systems that are affected by sex. While current data are somewhat limited and not in complete agreement, the majority of studies show that apparent cytochrome P450 (CYP) 3A4 activity is higher in women than in men, whereas the activity of many other systems involved in drug metabolism may be higher in men than in women. Women and men also show different pharmacodynamic responses to a variety of drugs. While the clinical significance of these sex differences remains to be determined, we anticipate that they will be most important in the administration of drugs that have a narrow therapeutic range. In addition, sex differences in drug metabolism may be involved in the higher incidence of adverse reactions to drugs in women compared with men. Further research is needed to determine the scope and significance of these sex differences. Female-specific issues such as pregnancy, menopause, oral contraceptive use and menstruation may also have profound effects on drug metabolism. These effects can often be clinically important. Pregnancy may increase the elimination of antiepileptic agents, reducing their efficacy. Oral contraceptive use can interfere with the metabolism of many drugs and, conversely, certain drugs can impair contraceptive efficacy. More research is needed to determine the impact of menopause, hormone replacement and menstruation on drug therapy.

Gender Effects in Pharmacokinetics and Pharmacodynamics

The dynamic physiological changes that occur in the maternal-placental-fetal unit during pregnancy influence the pharmacokinetic processes of drug absorption, distribution and elimination. Pregnancy-induced maternal physiological changes may affect gastrointestinal function and hence drug absorption rates. Ventilatory changes may influence the pulmonary absorption of inhaled drugs. As the glomerular filtration rate usually increases during pregnancy, renal drug elimination is generally enhanced, whereas hepatic drug metabolism may increase, decrease or remain unchanged. A mean increase of 8L in total body water alters drug distribution and results in decreased peak serum concentrations of many drugs. Decreased steady-state concentrations have been documented for many agents as a result of their increased clearance. Pregnancy-related hypoalbuminaemia, leading to decreased protein binding, results in increased free drug fraction. However, as more free drug is available for either hepatic biotransformation or renal excretion, the overall effect is an unaltered free drug concentration. Since the free drug concentration is responsible for drug effects, the above mentioned changes are probably of no clinical relevance. The placental and fetal capacity to metabolise drugs together with physiological factors, such as differences acid-base equilibrium of the mother versus the fetus, determine the fetal exposure to the drugs taken by the mother. As most drugs are excreted into the milk by passive diffusion, the drug concentration in milk is directly proportional to the corresponding concentration in maternal plasma. The milk to plasma (M : P) ratio, which compares milk with maternal plasma drug concentrations, serves as an index of the extent of drug excretion in the milk. For most drugs the amount ingested by the infant rarely attains therapeutic levels.

Pharmacokinetic Changes During Pregnancy and Their Clinical Relevance

Clinical Pharmacology and Therapeutics (1993) 53, 503–514; doi:10.1038/clpt.1993.63

The use of caffeine for enzyme assays : a critical appraisal

Most individuals adjust their caffeine intake according to the objective and subjective effects induced by the methylxanthine. However, to reach the desired effects, the quantity of caffeine consumed varies largely among individuals. It has been known for decades that the metabolism, clearance, and pharmacokinetics of caffeine is affected by many factors such as age, sex and hormones, liver disease, obesity, smoking, and diet. Caffeine also interacts with many medications. All these factors will be reviewed in the present document and discussed in light of the most recent data concerning the genetic variability affecting caffeine levels and effects at the pharmacokinetic and pharmacodynamic levels that both critically drive the level of caffeine consumption. The pharmacokinetics of caffeine are highly variable among individuals due to a polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. Moreover there is a polymorphism at the level of another critical enzyme, N-acetyltransferase 2. At the pharmacodynamic level, there are several polymorphisms at the main brain target of caffeine, the adenosine A2A receptor or ADORA2. Genetic studies, including genome-wide association studies, identified several loci critically involved in caffeine consumption and its consequences on sleep, anxiety, and potentially in neurodegenerative and psychiatric diseases. We start reaching a better picture on how a multiplicity of biologic mechanisms seems to drive the levels of caffeine consumption, although much more knowledge is still required to understand caffeine consumption and effects on body functions.

https://pharmrev.aspetjournals.org/content/pharmrev/70/2/384.full.pdf

Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption

The pharmacokinetics of antiepileptic drugs may be altered during pregnancy, resulting in decline of serum concentrations and subsequent suboptimal control of seizures. We investigated changes which may occur during pregnancy in hepatic drug handling by comparing metabolic ratios of 15 pregnant epileptic women to 15 nonpregnant epileptic women, as well as 10 pregnant nonepileptic and 10 nonpregnant nonepileptic controls. We used the caffeine test to describe several enzyme activities: P450 1A2, xanthine oxidase, n-acetyltransferase and hydroxylation. For this end, ratios were calculated among a number of metabolites of the main demethylation pathway of caffeine. In addition, we measured D-glucaric acid excretion for specific characterization of antiepileptic drug metabolism. Paired comparison of epileptic women in late pregnancy and six to eight weeks post partum revealed statistically significant decreases in P450 1A2, xanthine oxidase and n-acetyltransferase activities, and a significantly increased hydroxylation activity during pregnancy. Twenty-one of the 30 epileptic women (70%) were found to be fast acetylators, whereas the normal distribution in the nonepileptic control groups was 50%. Excretion of D-glucaric acid was significantly increased in all epileptic patient groups as compared to the matched nonepileptic control groups. Importantly, it was also significantly increased in the pregnant nonepileptic control group as compared to the nonpregnant nonepileptic women. Overall, our results suggest that enzymatic pathways involved in antiepileptic drug metabolism tend to be increased during pregnancy as a potential cause for observed lower serum concentrations of these drugs.

B Tang

Papers

Pregnancy-induced changes in drug metabolism in epileptic women.