Pharmacokinetics of prophylactic cefazolin in parturients undergoing cesarean delivery.

The objectives of this work were (i) to characterize the pharmacokinetics of cefazolin in pregnant women undergoing elective cesarean delivery and in their neonates; (ii) to assess cefazolin transplacental transmission; (iii) to evaluate the dosing and timing of preoperative, prophylactic administration of cefazolin to pregnant women; and (iv) to investigate the impact of maternal dosing on therapeutic duration and exposure in newborns. Twenty women received 1 g of cefazolin preoperatively. Plasma concentrations of total cefazolin were analyzed from maternal blood samples taken before, during, and after delivery; umbilical cord blood samples obtained at delivery; and neonatal blood samples collected 24 h after birth. The distribution volume of cefazolin was 9.44 liters. [corrected] The values for pre- and postdelivery clearance were 7.18 and 4.12 liters/h, respectively. Computer simulations revealed that the probability of maintaining free cefazolin concentrations in plasma above 8 mg/liter during scheduled caesarean surgery was <50% in the cord blood when cefazolin was administered in doses of <2 g or when it was administered <1 h before delivery. Therapeutic concentrations of cefazolin persisted in neonates >5 h after birth. Cefazolin clearance increases during pregnancy, and larger doses are recommended for surgical prophylaxis in pregnant women to obtain the same antibacterial effect as in nonpregnant patients. Cefazolin has a longer half-life in neonates than in adults. Maternal administration of up to 2 g of cefazolin is effective and produces exposure within clinically approved limits in neonates.

Mycophenolate mofetil enhances the negative effects of sirolimus and tacrolimus on rat kidney cell metabolism.

BACKGROUND AND PURPOSE: Mycophenolate mofetil (MMF) per se is not known to have negative effects on the kidney. MMF alone or in combination with sirolimus, can be the basis of calcineurin inhibitor (CNI)-free, kidney sparing drug protocols. However, long-term outcomes in patients on MMF/SRL seem to be inferior to those treated with regimens that include the CNI tacrolimus (TAC) due to an increased risk of allo-immune reactions. Interestingly, potential enhancement of the negative effects of SRL and TAC on the kidney by MMF has never been considered. EXPERIMENTAL APPROACH: It was our aim to study the effects of TAC, SRL and MMF alone and evaluate their interactions when combined on the rat kidney. For this purpose we used a comprehensive molecular marker approach including measurements of urinary 8-isoprostane concentrations (oxidative stress marker) and changes of urinary metabolite patterns ((1)H-NMR spectroscopy) and comparing these markers to renal function (glomerular filtration rate (GFR)) and morphologic alterations (histology). KEY RESULTS: While MMF alone did not impact GFR, its interaction with SRL and TAC led to a significant decrease of rats' renal function. The decline went in parallel with a significant increase in urinary isoprostane concentrations and an enhancement of negative effects on urinary metabolite patterns. CONCLUSIONS: In broad summary, the present study showed that MMF may enhance the negative effects of TAC on kidney function and may even display nephrotoxic properties when combined with SRL.