Journal of Antimicrobial Chemotherapy (1991) 28, 419-^23

Pharmacokinetics of piperadllin during pregnancy A. Heikkflfi and R. Erkkola

Department of Obstetrics and Gynecology, Turku University Central Hospital, SF-20520 Turku, Finland

Introduction The pregnant and parturient woman is subject to many physiological alterations which also affect the pharmacokinetics of many drugs (Parker, 1984). These physiological changes include an increase in plasma volume of approximately 50%, 25-50% increase in renal blood flow and a 50% increase in glomerular filtration rate. Yet the pharmacokinetics of acylureidopenicillins in pregnancy have been poorly studied, even though these drugs have been used effectively in the treatment of various infections during pregnancy. In particular, piperacillin has been used to treat chorionamnionitis and for prophylaxis in caesarean sections (Faro et al., 1990). The only studies of pharmacokinetics of piperacillin during pregnancy we are aware of snowed no difference in piperacillin concentration when pregnant subjects were compared to non-pregnant ones (Voigt, Schroder & Peiker, 1985). In a placental perfusion study, about seven per cent of maternal concentration was shown to pass the placenta (Akbaraly et al., 1985). This study was designed to evaluate the pharmacokinetics and transplacental passage of piperacillin. Materials and methods The study group A consisted of eight parturient women, who delivered by caesarean section due to secondary arrest of labour (« = 7) or threatening fetal asphyxia (n = 1). Six of the mothers had an uncomplicated pregnancy and two had mild pregnancyinduced hypertension. The reference group B consisted of five non-pregnant female 419 0305-7453/91/090419 + 0$ $02.00/0

© 1991 The British Society for Antimicrobial Chemotherapy

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The pharmacokinetics of piperarillin during pregnancy were investigated. Eight pregnant women received 4 g of piperacillin intravenously before caesarean section. Likewise, five non-pregnant subjects of child bearing age received the same dose before a gynaecological operation. The mean peak plasma concentrations of piperacillin were 87-5 and 172-2 mg/L for the pregnant and non-pregnant patients, respectively. The mean umbilical vein concentration was 9-7 mg/L; the mean umbilical artery concentration was 7-4 mg/L and the amniotic fluid concentration 6-8 mg/L. The feto-materaal ratio at the time of caesarean section was 0-27. Pharmacokinetic parameters of piperacillin indicate larger volumes of distribution and higher clearance rates during pregnancy compared with the non-pregnant state. The altered pharmacokinetics of piperacillin during pregnancy suggest that higher doses may be required for effective treatment of serious infections in pregnant women near term.

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A. HdkklU and R. Erkkoh

patients of child bearing age undergoing a gynaecological operation for a benign disease. The patients had had no regular medication and no antibiotics for at least seven days. For caesarean sections and gynaecological operations anaesthesia and analgesics were given as usual. The study protocol was approved by the joint Committee of Ethics of the University of Turku and the University Central Hospital of Turku and all patients gave their informed consent for participation in the study. Although the pregnant subjects were expected to have a higher body weight than the non-pregnant ones, the difference between the mean weights was not statistically significant (P = 0-065). Study design

Determination of piperacillin concentration Piperacillin concentrations were determined by high performance liquid chromatography (Aravind, Miceli & Kauffman, 1982). The analyses were performed using a Shimadzu LC-4A chromatograph equipped with a SPD-2AS data processor. The column used was Waters yBondapak C18, 30 cm x 2 mm (Waters Assoc., Milford, MA, U.S.A.). The flow inserts used were packed with yBondapak C18 (Guard-PAK, Waters Assoc.). The lowest detectable level of piperacillin was 0-03 mg/L. The intraassay coefficient of variation was 5-3% (1-26—11-8%) and interassay coefficient of variation 404% (0-7-0-86%), respectively.

Statistics The pharmacokinetic parameters were calculated by a Siphar pharmacokinetic computer program. The mean values for various pharmacokinetic parameters were compared using the Mann-Whitney U-test. Results The mean peak plasma concentrations were lower and the slope of elimination steeper (Figure) for the pregnant patients than for the nonpregnant ones. The pharmacokinetic parameters for the two groups are presented in Table I. The total clearance of piperacillin was significantly (P < 0-01) faster in the pregnant than in nonpregnant group. Furthermore, corrected total clearance and uncorrected volumes of distribution were significantly (P < 0-05) different when the groups were compared. The corrected volumes of distribution were larger and the half-lives slightly shorter in the pregnant group, yet the differences were not statistically significant. Twenty seven per cent of the drug was excreted unchanged in the urine during 8 h. The mean concentration of

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All patients received 4 g of piperacillin (Pipril, Lederle Labs. New York, NY, USA) as an intravenous infusion over 20 min via an infusion pump. The infusion was started 20 min prior to the operation. The plasma samples were collected from the contralateral arm vein at the start of the infusion and at 2, 5, 10, 15, 30, 45, 60, 120, 180, 300 and 480 min after the end of the infusion. The urine samples were collected in fractions at 0, 0-2, 2-5 and 5-8 h, and stored at -70°C. At caesarean section, samples of the umbilical vein and artery and amniotic fluid were obtained at the time of birth. Initially, blood was preserved on ice, and after separation, stored at — 70°C.

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Piperacillin in pregnancy

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Flgnre. Semilogarithmk time-concentration curves (-S.D.) for pregnant ( • ) and non-pregnant (O) subjects.

piperacillin in umbilical vein plasma was 9-7 (S.E.M. 2-5). The mean ratio of umbilical vein concentration to piperacillin concentration in the maternal plasma at the time of birth was 0-27. The amniotic fluid mean concentration was 3-94 (S.E.M. 1-8) (Table II). Discussion The pharmacokinetics of several antibiotics are greatly altered during pregnancy (Philipson, 1982). Therapeutic failures may be due to inadequate serum concentration. Table L Pharmacokinetic parameters for pregnant (n =» 8) and non-pregnant (n — 5) subjects (Mean, S.E.M.) Parameter Weight T t Peak concentration Total clearance Corrected total clearance Volume of distribution Corrected volume of distribution

Pregnant 82 46-5 87-5 1538-0 19-4 67-6 1-06

(6-4) (104) (12-8) (362) (51) (11-8) (02)

Non-pregnant 63 53-7 172-2 54O0 8-9 41-9 067

(1-4) (4-6) (23-5) (75) (1-3) (6-2) (01)

Difference NS.P-O065 NS, P •» 0524 P P P

Pharmacokinetics of piperacillin during pregnancy.

The pharmacokinetics of piperacillin during pregnancy were investigated. Eight pregnant women received 4 g of piperacillin intravenously before caesar...
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