Placental transfer of clindamycin and gentamicin in term pregnancy

Weinstein, Allan J.; Gibbs, Ronald S.; Gallagher, Mollie

doi:10.1016/s0002-9378(16)33336-1

Cited by 82 publications

(35 citation statements)

References 8 publications

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“…In contrast, Philipson et al (27) found ratios of 0.18 and 0.25 after administration of an oral dose of clindamycin in women with gestational ages of 10 to 22 weeks during therapeutic abortions. Our values are comparable to the ratios reported by Weinstein et al (34). The low values reported by Philipson et al (27) might be explained by the low gestational age.…”

Section: Discussionsupporting

confidence: 89%

“…The pharmacokinetic parameter estimate for CL for the mothers resulted in a value less than the published values (10.0 liter/h for our study versus values of 19.8 to 26.4 liter/h in the literature [10,12,28,33,34]). Two previous studies determined the ratio of umbilical cord blood and maternal blood (27,34). Weinstein et al found a ratio of 0.46 after intravenous administration during delivery by cesarean section (34).…”

Section: Discussioncontrasting

confidence: 87%

“…Two previous studies determined the ratio of umbilical cord blood and maternal blood (27,34). Weinstein et al found a ratio of 0.46 after intravenous administration during delivery by cesarean section (34). In contrast, Philipson et al (27) found ratios of 0.18 and 0.25 after administration of an oral dose of clindamycin in women with gestational ages of 10 to 22 weeks during therapeutic abortions.…”

Section: Discussionmentioning

confidence: 98%

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Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period

Muller

Mouton

Oostvogel

et al. 2010

Antimicrob Agents Chemother

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The study presented here was performed to determine the pharmacokinetics of intravenously administered clindamycin in pregnant women. Seven pregnant women treated with clindamycin were recruited. Maternal blood and arterial and venous umbilical cord blood samples were obtained. Maternal clindamycin concentrations were analyzed by nonlinear mixed-effects modeling with the NONMEM program. The data were best described by a linear three-compartment model. The clearance and the volume of distribution at steady state were 10.0 liters/h and 6.32 ؋ 10 3 liters, respectively. Monte Carlo simulations were performed to determine the area under the concentration curve (AUC) for the free (unbound) drug (f) in maternal serum for 24 h divided by the MIC (fAUC 0-24 /MIC). At a MIC of 0.5 mg/liter, which is the EUCAST breakpoint, the attainment at the lower 95% confidence interval (CI) was 24.6 if the level of protein binding was 65%, and this value concurred well with the target value of 27. However, for higher degrees of protein binding, as has been described in the literature, the attainment was lower, down to 10.2 for a protein binding level of 85% (lower 95% CI). The concentrations in umbilical cord blood were lower than those in maternal blood. The concentration-time profiles in maternal serum indicate that the level of exposure to clindamycin may be too low in these patients. Together with the lower concentrations in umbilical cord blood, this finding suggests that the current dosing regimen may not be adequate to protect all neonates from group B streptococcal disease.

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Section: Discussionsupporting

confidence: 89%

Section: Discussioncontrasting

confidence: 87%

Section: Discussionmentioning

confidence: 98%

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Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period

Muller

Mouton

Oostvogel

et al. 2010

Antimicrob Agents Chemother

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“…In our study, cells were incubated with gentamicin concentrations that are almost 1000-fold higher than what the placenta would be exposed to in clinical settings (8,(12)(13)(14). While these levels would seem clinically irrelevant, they provide a proof of concept.…”

Section: Discussionmentioning

confidence: 99%

The Role of Megalin in the Transport of Gentamicin Across BeWo Cells, an In Vitro Model of the Human Placenta

Akour

Kennedy

Gerk

2015

AAPS J

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Abstract. Aminoglycosides (AG) are known to readily cross the placenta, although the mechanisms responsible for placental transport have not been characterized. Megalin is expressed in human placenta, and it is reasonable to speculate, given its role in renal AG uptake, that it is similarly involved in placental transport. However, the role of megalin in placental AG uptake has not been established. An in vitro model to study megalin-mediated placental transport has also not been previously described. The objectives of this study, therefore, were to evaluate the human choriocarcinoma (BeWo) cell line as a model to study megalin-mediated placental transport and to assess the uptake kinetics of gentamicin, an AG antibiotic, using this in vitro model. BeWo cells were grown on Transwell® plates, and megalin expression and functional activity were assessed. Uptake of 3 H-gentamicin was also evaluated in the presence and absence of megalin inhibitors. Expression of megalin protein and mRNA in BeWo cells were confirmed via immunoblot and qPCR analysis. Uptake of fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (BSA) (a megalin substrate) was time-, concentration-, and temperature-dependent consistent with a transporter-mediated process. FITC-BSA uptake was also significantly reduced in the presence of unlabeled gentamicin (a megalin substrate) and sodium maleate (to induce megalin shedding) suggesting that megalin is functionally active in BeWo cells. Gentamicin uptake exhibited time and temperature dependence, saturability and Michaelis-Menten kinetics, all of which suggest a transporter-mediated process. Gentamicin uptake was also significantly reduced in the presence of the megalin inhibitors RAP and EDTA suggesting that megalin is likely involved in gentamicin uptake.

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“…Like many other drugs, these compounds are known to cross the human placenta (5,14,16). It is well established that, in adult human and animal kidneys, aminoglycosides accumulate and are nephrotoxic, but in the fetus, their behavior has received little attention.…”

mentioning

confidence: 99%

Kinetics of gentamicin in plasma of nonpregnant, pregnant, and fetal guinea pigs and its distribution in fetal tissues

Lelièvre-Pégorier¹,

Sakly²,

Meulemans³

et al. 1985

Antimicrob Agents Chemother

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Nonpregnant and pregnant guinea pigs in the last third of gestation were injected intramuscularly with 4 mg of gentamicin per kg, and drug concentrations in plasma were determined by radioimmunoassay at several intervals after injection. The maximum gentamicin concentration was significantly lower in pregnant than in nonpregnant animals (14.6 ± 0.7 ,ug/ml versus 21.6 ± 0.7 ,ug/ml), and the peak time occurred significantly later (0.57 ± 0.12 h versus 0.13 ± 0.02 h). Four hours after gentamicin injection, drug concentrations in plasma were 2.1 ± 0.8 and 0.3 ± 0,1 ,ug/ml in pregnant and nonpregnant animals, respectively. Pregnant animals therefore eliminated the drug from their plasma more slowly. These data provide good evidence that the kinetics of plasma gentamicin varies in pregnant females because its volume of distribution was larger in pregnant than in nonpregnant animals. Detectable but small amounts of gentamicin (c 0.50 ,zg/ml) were found in the plasma of 46 of 57 fetuses. However, no net variations in these concentrations were observed during the period between 15 min and 6 h after injection to the mother. Gentamicin concentrations were also determined in the kidneys, liver, lungs, heart, and brain of fetal guinea pigs after administration to their mothers of one daily injection of 4 mg/kg for 7 days. Gentamicin was present in all these fetal organs; however, as in the adult organs, the kidneys contained far more than any of the others. Gentamicin concentrations were not significantly different in the kidney cortex and medulla (1.79 ± 0.16 versus 1.48 + 0.92 ,Lg/g), indicating that, contrary to what is observed for adults, renal accumulation of gentamicin in the fetus does not occur preferentially in the cortex.

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Placental transfer of clindamycin and gentamicin in term pregnancy

Cited by 82 publications

References 8 publications

Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period

Pharmacokinetics of Clindamycin in Pregnant Women in the Peripartum Period

The Role of Megalin in the Transport of Gentamicin Across BeWo Cells, an In Vitro Model of the Human Placenta

Kinetics of gentamicin in plasma of nonpregnant, pregnant, and fetal guinea pigs and its distribution in fetal tissues

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