Kersti Oselin

Quantitative determination of the human MRP1 and MRP2 mRNA expression in FACS-sorted peripheral blood CD4+, CD8+, CD19+, and CD56+cells

Objectives: ATP‐binding cassette (ABC) transporters extrude a wide variety of endogenous and exogenous compounds. In cancer cells, they are known to confer multidrug resistance. The aim of the present study was to determine the expression of the multidrug resistance‐associated protein 1 (MRP1) and 2 (MRP2), which are members of the subfamily C of the ABC transporters family, in human hematopoietic cells.

Short versus Long Infusion of Meropenem in Very-Low-Birth-Weight Neonates

ABSTRACT Prolonged infusion of meropenem has been suggested in studies with population pharmacokinetic modeling but has not been tested in neonates. We compared the steady-state pharmacokinetics (PK) of meropenem given as a short (30-min) or prolonged (4-h) infusion to very-low-birth-weight (gestational age, <32 weeks; birth weight, <1,200 g) neonates to define the appropriate dosing regimen for a phase 3 efficacy study. Short (n = 9) or prolonged (n = 10) infusions of meropenem were given at a dose of 20 mg/kg every 12 h. Immediately before and 0.5, 1.5, 4, 8, and 12 h after the 4th to 7th doses of meropenem, blood samples were collected. Meropenem concentrations were measured by ultrahigh-performance liquid chromatography. PK analysis was performed with WinNonlin software, and modeling was performed with NONMEM software. A short infusion resulted in a higher mean drug concentration in serum (Cmax) than a prolonged infusion (89 versus 54 mg/liter). In all but two patients in the prolonged-infusion group, the free serum drug concentration was above the MIC (2 mg/liter) 100% of the time. Meropenem clearance (CL) was not influenced by postnatal or postmenstrual age. In population PK analysis, a one-compartment model provided the best fit and the steady-state distribution volume (Vss) was scaled with body weight and CL with a published renal maturation function. The covariates serum creatinine and postnatal and gestational ages did not improve the model fit. The final parameter estimates were a Vss of 0.301 liter/kg and a CL of 0.061 liter/h/kg. Meropenem infusions of 30 min are acceptable as they balance a reasonably high Cmax with convenience of dosing. In very-low-birth-weight neonates, no dosing adjustment is needed over the first month of life.

Inhibition of Human Thiopurine S-Methyltransferase by Various Nonsteroidal Anti-inflammatory Drugs in Vitro: A Mechanism for Possible Drug Interactions

Thiopurine S-methyltransferase (TPMT) is a biotransformation phase II enzyme responsible for the metabolic inactivation of thiopurine drugs. The present study was carried out to investigate the inhibitory potential of 15 nonsteroidal anti-inflammatory drugs (NSAIDs) on human TPMT activity in vitro. TPMT activity was measured in pooled human erythrocytes in the absence and presence of various NSAIDs using the previously published high-performance liquid chromatography-UV method. To determine the inhibition type and Ki value for each compound, we performed kinetic analysis at five different inhibitor concentrations close to the IC50 value obtained in preliminary experiments. Naproxen (Ki = 52 μM), mefenamic acid (Ki = 39 μM), and tolfenamic acid (Ki = 50 μM) inhibited TPMT activity in a noncompetitive manner. The estimated Ki values for the inhibition of TPMT by ketoprofen (Ki = 172 μM) and ibuprofen (Ki = 1043 μM) indicated that the propionic acid derivatives were relatively weak inhibitors of TPMT. Our results suggest that coadministration of thiopurines and various NSAIDs may lead to drug interactions.

Pharmacokinetics of Penicillin G in Very-Low-Birth-Weight Neonates

ABSTRACT Data on the pharmacokinetics (PKs) of penicillin G (PEN) in neonates date back to the 1970s and do not include data for very-low-birth-weight (VLBW) neonates. The aim of this study was to describe the steady-state PKs and to establish an optimal regimen for the dosing of PEN in neonates with gestational ages of less than 28 weeks and birth weights of less than 1,200 g. Two PEN dosing regimens were studied: 50,000 IU (30 mg)/kg of body weight every 12 h (q12h) (group 1; n = 9) and 25,000 IU (15 mg)/kg q12h (group 2; n = 9). Samples for PK analysis were drawn before the injection of PEN and at 2 and 30 min and 1.5, 4, 8, and 12 h after intravenous injection of the third to eighth PEN doses. The PEN concentration was measured by a high-performance liquid chromatography with UV detection technique. The median peak and trough concentrations of PEN were 147 μg/ml (lower and upper quartiles, 109 and 157 μg/ml, respectively) and 7 μg/ml (lower and upper quartiles, 5 and 13 μg/ml, respectively) after administration of the dose of 50,000 IU and 59 μg/ml (lower and upper quartiles, 53 and 78 μg/ml, respectively) and 3 μg/ml (lower and upper quartiles, 3 and 4 μg/ml, respectively) after administration of the dose of 25,000 IU. The PEN half-life (median and lower and upper quartiles for group 1, 3.9 h and 3.3 and 7.0 h, respectively; median and lower and upper quartiles for group 2, 4.6 h and 3.8 and 5.6 h, respectively) was longer in VLBW neonates than in adults and term infants. PEN renal clearance correlated with creatinine clearance (R2 = 0.309596; P = 0.038). Only a median of 34% (lower and upper quartiles, 28 and 37%, respectively) of the administered dose was excreted in urine within the following 12 h. We conclude that in VLBW infants a PEN dose of 25,000 IU (15 mg)/kg q12h is safe and sufficient to achieve serum concentrations above the MIC90 for group B streptococci for the entire dosing interval.

Thiopurine S-methyltransferase (TPMT) pharmacogenetics: three new mutations and haplotype analysis in the Estonian population.

Abstract Background: Thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme involved in the metabolism of thiopurine drugs. To date, at least 25 single nucleotide polymorphisms have been reported in the TPMT gene, 23 of these are associated with reduced enzyme activity. Methods: The aim of the present study was to sequence the whole coding region of TPMT (exons 3–10) to identify known and novel TPMT sequence variants amongst healthy Estonians. Erythrocyte TPMT activity was also measured to carry out a genotype-phenotype comparison. Results: A total of 21 subjects were heterozygous for known TPMT alleles (*2, *3A, *3C, *9, *12). Several other previously described intronic and exon polymorphisms were identified. Three novel mutations were detected −30T>A in exon 3, 10A>G in intron 3, and 145A>G in intron 10. Association analysis revealed four markers (114T>A, 94T>A, 460G>A, 719A>G) whose frequencies were significantly different in intermediate (enzyme activity ≤60 ng/mL/h) methylators compared to normal (enzyme activity 61–139 ng/mL/h) and high (enzyme activity ≥140 ng/mL/h) methylators (p<0.001). Haplotype analysis found one haplotype to be associated with intermediate TPMT activity. Conclusions: Our results point to several markers that predict reduced enzyme activity. None of the identified markers were associated with high enzyme activity. Clin Chem Lab Med 2008;46:974–9.

Blood Loss Related to Participation in Pharmacokinetic Study in Preterm Neonates

Background: The amount of blood that can be safely drawn from a preterm neonate for scientific purposes is poorly established. Objectives: To provide scientific evidence on the amount of blood that can be drawn from very low birth weight (VLBW) neonates for study purposes. Methods: We performed a post-hoc analysis of a pharmacokinetic (PK) study of penicillin-G, enrolling 18 neonates with a birth weight of <1,200 g, gestational age of <28 weeks and postnatal age of <5 days, with a risk of early onset sepsis. A median of 2.3 ml/kg of blood was collected from each neonate for the PK analysis. Hemoglobin (Hgb), hematocrit (Ht), basic hemodynamic parameters, total fluid intake, number of blood component transfusions and number of blood analysis for clinical indications were recorded. The control group consisted of 35 gestational age-, postnatal age- and birth weight-matched neonates who had not participated in a PK study. Results: We did not observe significant differences in any studied safety parameter, including Hgb and Ht values, between the two groups. Median number of blood component transfusions (n = 2 in both groups), median volume of transfused red blood cells (22 vs. 24 ml/kg in study vs. control group) and total daily fluid requirement were similar. The median calculated blood loss on clinical indications was 1.9 ml/24 h in the control group and 1.66 ml/24 h in the study group. Conclusions: In VLBW neonates, up to 2.3 ml/kg of blood (corresponding to 2.4% of calculated circulating blood volume) can be drawn for scientific purposes without compromising basic hemodynamic parameters, Hgb and Ht values, blood component transfusions or fluid requirements.

Pharmacokinetics and pharmacodynamics of piperacillin/tazobactam during high volume haemodiafiltration in patients with septic shock

The purpose of the study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of piperacillin and tazobactam during high‐volume haemodiafiltration (HVHDF).

Pharmacokinetics of doripenem during high volume hemodiafiltration in patients with septic shock

Pharmacokinetics (PK) of doripenem was determined during high volume hemodiafiltration (HVHDF) in patients with septic shock. A single 500 mg dose of doripenem was administered as a 1 hour infusion during HVHDF to 9 patients. Arterial blood samples were collected before and at 30 or 60 minute intervals over 8 hours (12 samples) after study drug administration. Doripenem concentrations were determined by ultrahigh performance liquid chromatography‐tandem mass spectrometry. Population PK analysis and Monte Carlo simulation of 1,000 subjects were performed. The median convective volume of HVHDF was 10.3 L/h and urine output during the sampling period was 70 mL. The population mean total doripenem clearance on HVHDF was 6.82 L/h, volume of distribution of central compartment 10.8 L, and of peripheral compartment 12.1 L. Doses of 500 mg every 8 hours resulted in 88.5% probability of attaining the target of 50% time over MIC for bacteria with MIC = 2 µg/mL at 48 hours, when doubling of MIC during that time was assumed. Significant elimination of doripenem occurs during HVHDF. Doses of 500 mg every 8 hours are necessary for treatment of infections caused by susceptible bacteria during extended HVHDF.