Transplacental passage of primidone

Martínez, Guillermo Alcaín; Snyder, Russell D.

doi:10.1212/wnl.23.4.381

Cited by 20 publications

(3 citation statements)

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“…As expected, similar concentrations of this drug were found in maternal serum and umbilical cord serum (see table VIII). Similar findings were reported by Martinez and Snyder (1973), although administration of single primidone doses resulted in greatly varying drug concentrations at the time of birth, and by Niebyl et aI. Similar findings were reported by Martinez and Snyder (1973), although administration of single primidone doses resulted in greatly varying drug concentrations at the time of birth, and by Niebyl et aI.…”

Section: Placental Transfer At Termsupporting

confidence: 75%

Anticonvulsants during Pregnancy and Lactation

Nau

Kuhnz

Egger

et al. 1982

Clinical Pharmacokinetics

149

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Few data are available on placental transfer of anticonvulsants during early pregnancy. Nevertheless, it has been demonstrated that at this early stage of gestation, considerable amounts of phenytoin, primidone/phenobarbitone and carbamazepine as well as some of their metabolites are already present in fetal tissues. Potentially reactive metabolites of anticonvulsants can be formed by the fetal liver and accumulate in some organs. At term, most anticonvulsants are present in neonatal plasma in concentrations similar to those in maternal plasma. Valproic acid, on the other hand, can accumulate in fetal blood, for still unknown reasons. Elimination by the neonate is variable and is dependent on several factors, such as clinical state, pre- or perinatal enzyme induction, absorption of the drugs and their plasma protein binding. Neonatal acquisition of anticonvulsants via breast-feeding does not seem to be harmful for the neonate. In the case of phenobarbitone, however, the drug may accumulate in nursing neonates to levels approaching or even exceeding those of their mothers. Significant drug levels can also build up in neonates and infants nursed by carbamazepine- and ethosuximide-treated mothers. This review contains relevant pharmacokinetic data on anticonvulsant drugs widely used during pregnancy and the neonatal period. The differences between pregnant and non-pregnant adults as well as between neonates and older age groups are emphasized. Some pharmacokinetic data are correlated with clinical manifestations, such as seizure frequency, neonatal depression and withdrawal symptoms.

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Section: Placental Transfer At Termsupporting

confidence: 75%

Anticonvulsants during Pregnancy and Lactation

Nau

Kuhnz

Egger

et al. 1982

Clinical Pharmacokinetics

149

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“…A great advantage has been the development of techniques for the sampling of blood from the cord vein and artery while the fetus is still in utero, We refer to 3 studies carried out with this methodology,l73-75) The major advantages of this technique are that blood may be sampled from mid-gestation to term at the appropriate times, on the basis of the pharmacokinetic profile of the drug, without analysis being linked with the time of delivery, However, two main problems remain to be solved: (i) the selection of the drug to be studied; and (ii) the design of the experimental protocoL Variability in the extent of drug transfer remains an unsolved problem which deserves to be investigated for those drugs that may be harmful to the fetus and for those that are poorly transferred, such as several antimicrobial agents, but should reach appropriate concentrations in the fetus , For many drugs a variable transfer has been described, However, for oxytetracycline [76] primidone [77) and zidovudine [75.78) the variability was so high that makes it difficult to predict if the drug concentration in the cord blood is higher or lower © Adis International limited. All rights reserved .…”

Section: 3 Newer Methodological Aspects Of the Placental Transfer Ofmentioning

confidence: 99%

Placental Transfer of Drugs Administered to the Mother

Pacifici

Nottoli

1995

Clinical Pharmacokinetics

282

119

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Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs. In this review drugs are classified according to their type of transfer across the placenta. Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed 'complete'. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in fetal than maternal plasma. It is said that these drugs have an 'exceeding' transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent transfer varies considerably. The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.

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“…Thus pregnanediol values for patients taking this drug cannot be measured unless the assay procedure is modified so that an internal standard other than progesterone is used. Phenylethylmalondiamide (PEMA) and phenobarbital, which are the 2 principal metabolites of primidone (Gallagher et aI., 1973) are not detected by the Cox procedure. In relation to the use of primidone in women intending to become pregnant, it should be noted that this drug readily crosses the placenta, and may even cause withdrawal symptoms in the baby shortly after birth (Martinez and Snyder, 1973). High concentrations of primidone (4.6-10.5 mg/l) and its metabolite PEMA (1.3-2.4 mg/l) have also been found in the breast milk of women prescribed the drug (Horning et al, 1975).…”

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confidence: 99%