The purpose of this study was to evaluate the role of sequence variants in the CYP2C8, ABCB1 and CYP3A4 genes and the CYP3A4 phenotype for the pharmacokinetics and toxicity of paclitaxel in ovarian cancer patients. Thirty-eight patients were treated with paclitaxel and carboplatin. The genotypes of CYP2C8*1B, *1C, *2, *3, *4, *5, *6, *7, *8 and P404A, ABCB1 G2677T/A and C3435T, as well as CYP3A4*1B, were determined by pyrosequencing. Phenotyping of CYP3A4 was performed in vivo with quinine as a probe. The patients were monitored for toxicity and 23 patients underwent a more extensive neurotoxicity evaluation. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than most other ABCB1 variants. A lower clearance of paclitaxel was found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. In addition, the CYP3A4 enzyme activity in vivo affected which metabolic pathway was dominant in each patient, but not the total clearance of paclitaxel. The exposure to paclitaxel correlated to the degree of neurotoxicity. Our findings suggest that interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.Paclitaxel in combination with carboplatin is the standard chemotherapy for ovarian cancer. Carboplatin doses are adjusted according to the renal function, whereas paclitaxel is used in standardized doses according to body surface area. The pharmacokinetics and the response to paclitaxel treatment vary greatly among individuals and one factor of importance for these differences might be the genetic variability. Our belief is that it would be important to be able to predict the highest yet safe starting dose for each individual to avoid undertreatment. Understanding the mechanisms behind the interindividual differences in the pharmacokinetics of paclitaxel should be the foundation for establishing individual dosages.It has been suggested that the pharmacokinetics of paclitaxel are affected by several proteins, such as metabolic enzymes and drug transporters [1]. Systemic elimination of paclitaxel occurs by hepatic metabolism involving the cytochrome P450 (CYP) enzymes, CYP3A4 and CYP2C8 [2]. Paclitaxel is converted to p -3 ′ -hydroxypaclitaxel by CYP3A4 and CYP2C8 catalyzes the formation of 6 α -hydroxypaclitaxel [3,4]. These metabolites can be further oxidized to 6 α -, p -3 ′ -dihydroxypaclitaxel [4,5]. All three metabolites are less potent than the parent compound in inhibiting cell growth in vitro [6,7]. Several single nucleotide polymorphisms (SNP) have been reported in the CYP2C8 gene and some alleles (*2, *3, *7, *8 and P404A) have been associated with decreased 6 α -hydroxypaclitaxel production in vitro [8][9][10][11]. The CYP2C8*5 allele, a premature stop-codon, is also expected to encode an inactive protein [12]. However, the effects of the polymorphisms on paclitaxel pharmacokinetics in vivo are still ...

Hospital birth records were sought for 104 men from a pool of male army conscripts with "normal" or "high" blood pressure when measured at 28 years of age. Of 77 men whose birth weight and date of the mother's last menstrual period before the pregnancy could be found, 25 had a resting diastolic blood pressure of ¢90 mm Hg.

Single dose pharmacokinetics of 75 mg aspirin was investigated in two groups of ten women with clinically normal pregnancies. Eleven non-pregnant subjects in the same age were controls. In group A, gestational age was 27-30 completed weeks, and in group B, 36-39 weeks. Venous blood samples were taken before and up to 240 minutes after the intake of the aspirin. Liquid chromatographic assays for acetylsalicylic acid (ASA) and its metabolite, salicylic acid (SA), was performed. The pharmacokinetics of ASA and SA were similar in group A and B but pregnant subjects had a slower uptake and a lower peak level than controls. The late elimination phase for their compound did not differ between the groups. Nine pregnant women with normal pregnancies had their bleeding time measured by a modified Ivy technique using a Simplate II device before, at the end of, and two weeks after daily administration of 75 mg ASA for two weeks. All had a normal bleeding time before and two weeks after the end of the medication. Eight of the nine subjects had an increased bleeding time by Ivy tests, (p < 0.01) whereas the bleeding time assessed by Duke's method was within normal limits. These studies suggest that during pregnancy changes of the uptake rate and distribution volume modulate the pharmacokinetics of ASA and that this drug given in low dosage to gravidae marginally alters their platelet function.