Pharmacokinetics in pregnant women
Most organ systems are subject to physiological changes during pregnancy, and many of these may affect the pharmacokinetics of drugs. Reduced gastrointestinal motility and increased gastric pH may affect the absorption of drugs. Declining concentrations of drug binding proteins may, in combination with an increase in total body water and plasma volume, lead to higher distribution volumes and reduced serum concentrations of some drugs. The concentrations of albumin, which binds drugs that are weak acids, and of α1-acid glycoprotein, which binds drugs that are weak bases, decline. Changed activity of various hepatic drug-metabolising enzymes may result in reduced, unchanged or increased concentrations of drugs. The activity of both cytochrome P-450 (CYP)-enzymes and glucuronidation enzymes will be affected. Increased renal blood flow and a higher glomerular filtration rate will increase the excretion of drugs relying mainly on renal elimination. An overview of the main pharmacokinetic changes that occur during pregnancy is given in Figure 1 (2, 6, 7, 8). The changes will normally increase gradually throughout pregnancy, reach their maximum level in the second or third trimester and normalise within 1–2 weeks of delivery (2, 9).
Based on knowledge about the pharmacological properties of individual drugs and the physiological changes presented in Figure 1, one may attempt to estimate how pregnancy will affect maternal drug concentrations. As a rule of thumb, the drug's elimination route is the most crucial factor to consider. If the drug is mainly excreted unchanged through the kidneys, serum concentrations will often decline by almost 50 % during the pregnancy (Fig. 1, panel C) (6). If the drug is mainly eliminated by the liver, a concentration fall of the same magnitude (or greater) may occur, but the concentration may also remain unchanged, or in some cases increase (6). This depends on which enzyme or enzymes are most important for the metabolism of that particular drug, because changes in enzyme activity vary in magnitude and direction during pregnancy (Fig. 1, panel B) (6). Increased hepatic blood flow will also play a role in the degradation rate of some drugs.
Multiple physiological changes often affect a single drug during pregnancy, for instance with one drug-metabolising enzyme being inhibited while another is induced (this is the case for the antipsychotic drug olanzapine (10)), or with an increase in both hepatic and renal elimination (this is the case for the antiepileptic drug lamotrigine (11)). The net effect of these changes can be difficult to predict, and there can be considerable individual variation. Consequently, in order to provide the best possible dose recommendations for pregnant women, theoretical reflections concerning the drug's pharmacokinetic properties will not suffice. We need dedicated pharmacokinetic studies in pregnant women, and preferably serum concentration measurements from the patient in question. The clinical effect must also be closely monitored.