Clinical Pharmacokinetics in Pregnancy and Perinatology

Abstract

Ampicillin has been most thoroughly studied in regard to placental transfer. Both during the first/second trimester and at term, fetal drug levels rose slowly to reach values similar to those in the maternal circulation 1-3 h after maternal drug administration; thereafter, fetal drug levels exceeded corresponding maternal values. Amniotic fluid levels were low during early gestational periods; during late gestation these levels were significant and even exceeded corresponding maternal values 6-8 h after drug administration. Slow exchange rates and fetal micturation may be responsible for the elevated ampicillin levels during late gestation. Administration via the intramuscular (recommended with 0.5 g every 4-6 h) or intravenous routes, but not by the oral route, resulted in adequate drug levels. Because of increased plasma clearance of ampicillin during pregnancy, a dose increase in pregnant patients may be necessary to obtain adequate drug levels. Amoxillin and azidocillin have been suggested to give effective drug levels even after oral administration, except during labor. The fetal levels of epicillin and benzylpenicillin (Penicillin G) were lower than the corresponding maternal values; amniotic fluid concentrations of these two drugs were elevated during late, but very low during early gestation, similar to the situation with ampicillin. Methicillin and sulbenicillin were effectively transfered across the placenta (similar to ampicillin), while dicloxacillin was not. The low concentrations of dicloxacillin in the fetus and amniotic fluid may be the results of extensive protein binding (>90%) of this drug in maternal blood. Other highly bound penicillins such as cloxacillin and flucloxacillin have not yet been investigated in regard to placental transfer. Excretion of penicillins in human milk was usually very limited. Following therapeutic doses, the mean milk concentrations were 0.1-0.6 pg/ml for amoxicillin, 0.1-0.2 pg/ml for epicillin, about 0.5 pg/ml for sulbactam, 2-2.5 pg/ml for ticarcillin, and 0.1-0.4 pg/ml for aztreonam.

Clinical Pharmacology of the Perinatal Period and Early Infancy

“…Increased free fractions have been reported for theophylline, salicylic acid, digoxin, phenylbutazone, phenytoin, phenobarbitone, clonazepam, carbamazepine and various analgesic compounds (Aranda et al 1976;Bourgeois & Dodson 1983;Fredholm et al 1975;Gorodischer et al 1974;Groce et al 1985;Kuhnz et al 1984;Kurz et al 1977a,b;Meuldermans et al 1986;Nau 1985;Pacifici et al 1984;Wallin & Herngren 1985;Windorfer et al 1974;Yaffe & Stem 1976).…”

The Pharmacokinetics of Antiarrhythmic Agents in Pregnancy and Lactation

“…Since the pH in the fetus is slightly lower than the maternal plasma, the fetal-maternal concentration ratio for weakly basic drugs may be greater for the free drug than the total drug. Nau (1985) made estimations of fetal-maternal ratios for free and total drug concentrations based on formulae derived from the Henderson-Hasselbach equation (for basic drugs): where Ctr = concentration of free drug in the fetus; Cfm = maternal free drug concentration; Ctotf = total drug concentration in the fetus; Cwtm = maternal total drug concentration; fu = fraction unbound.…”

“…Assuming protein binding of 34% (0.66 unbound fraction) in the fetus and 63% (0.37 unbound fraction) in the maternal plasma, the free fetal-maternal ratio may be 1.4 while the fetal-maternal concentration ratio of total drug may be predicted at 0.8. However, due to the pH dependence of protein 266 binding, free drug concentrations of lignocaine cannot be predicted from total drug concentrations (Nau 1985). Several authors have reported higher fetal lignocaine concentrations in association with fetal acidosis (Biehl 1978;Brown 1976;Petrie 1974).…”

Pharmacokinetics of Oral Cefatrizine in Pregnant and Non-Pregnant Women with Reference to Fetal Distribution

“…A possible re-equilibration of the drug from the fetal to the maternal compartment could offer an explanation for the longer maternal elimination half-life, observed for CFT during pregnancy. Similarly to CFT, after the intramuscular administration of ampicillin (pK a = 2.5) fetal drug levels were initially found to be lower and then exceeded the corresponding maternal ones, with drug levels decreasing at a slower rate in the fetal blood than the maternal one [29] .…”