CYP3A5 genotype has significant effect on quinine 3-hydroxylation in Tanzanians, who have lower total CYP3A activity than a Swedish population.

OBJECTIVES: To study the correlation between CYP3A5 genotype and quinine 3-hydroxylation in black Tanzanian and Swedish Caucasians as well as to investigate the interethnic differences in CYP3A activity between the two populations. METHODS: Tanzanian (n=144) and Swedish (n=136) healthy study participants were given a single oral 250 mg dose of quinine hydrochloride and a 16-h post-dose blood sample was collected. The metabolic ratio of quinine/3-hydroxyquinine was determined in plasma by high-performance liquid chromatography. All the participants were genotyped for the known mutations of CYP3A5, which are relevant for the respective population. Correlation between quinine metabolic ratio and CYP3A5 genotype as well as the interethnic difference in CYP3A activity between the two populations was studied. RESULTS: Tanzanians had significantly higher (P<0.0001) mean quinine metabolic ratio (9.5+/-3.5) than Swedes (7.6+/-3.1). As expected, the frequency of high CYP3A5 expression alleles was higher in Tanzanians (51%) than in Swedes (7%). The mean+/-SD quinine metabolic ratio (10.7+/-3.9) in Tanzanians homozygous for low CYP3A5 expression gene was significantly higher than the corresponding mean metabolic ratio in participants heterozygous (9.5+/-3.3; P=0.02) or homozygous (8.1+/-3.1; P=0.002) for high expression CYP3A5 alleles, respectively. A tendency to higher quinine metabolic ratio in Swedes with low expression alleles compared with those with one or two high expression alleles was observed. Tanzanians homozygous for low CYP3A5 expression gene (i.e. only CYP3A4 is expressed) had significantly (P<0.0001) higher quinine metabolic ratio (10.7+/-3.9) than corresponding Swedes (7.7+/-3.1). CONCLUSIONS: Clear interethnic differences were observed in the activity of CYP3A between Tanzanians and Swedes. A significant association is noted between CYP3A5 genotype and quinine 3-hydroxylation in Tanzanians, indicating a significant contribution of CYP3A5 to total 3A activity. The CYP3A4 catalyzed hydroxylation of quinine (two low CYP3A5 expression alleles) was lower in Tanzanians than in Swedes.

Urinary and fecal excretion of topotecan in patients with malignant solid tumours.

PURPOSE: The objectives of the study were to determine the pharmacokinetics and routes of excretion of topotecan following intravenous or oral administration to patients with refractory solid tumours. METHODS: Patients were randomized to receive either oral (2.3 mg/m(2)) or intravenous (1.5 mg/m(2)) topotecan once daily for 5 days in course 1. Patients who received in course 1 oral topotecan received in course 2 intravenous topotecan on day 1 followed by oral topotecan on days 2 to 5. Patients who received in course 1 intravenous topotecan received in course 2 oral topotecan once daily for 5 days. Plasma pharmacokinetics were performed on day 1 of course 1 (all patients) and course 2 (only patients receiving intravenous topotecan on that day). In course 1, urine and feces were collected for up to 9 days after the first dosage. The amounts of topotecan and N-desmethyl topotecan in plasma, urine and feces were determined by validated high-performance liquid chromatographic assays. RESULTS: A total of 11 patients were enrolled in the study. Nine patients were evaluable for pharmacokinetics. Plasma pharmacokinetics were similar to those previously reported. The principal route of excretion was the urine, with approximately 49% of the intravenously administered topotecan dose and 20% of the oral dose collected in the urine as parent drug. Approximately 18% and 33% of the intravenous and oral dose, respectively, were recovered unchanged in the feces. Only small amounts of N-desmethyl topotecan were found in the excreta. CONCLUSIONS: Fecal and urinary excretion of unchanged topotecan were the major routes of topotecan elimination. Approximately 28% of the intravenous dose and 43% of the oral dose of topotecan were unaccounted for and eliminated through other routes.

Topoisomerase I levels in white blood cells of patients with ovarian cancer treated with paclitaxel-cisplatin-topotecan in a phase I study.

Topotecan stabilizes the topoisomerase I (Topo I) cleavable complex. We measured Topo I levels in white blood cells of patients with ovarian cancer treated with topotecan. Topotecan was given i.v. daily x 5 q 3 weeks in combination with paclitaxel (1 day before topotecan) and cisplatin (just prior topotecan). Our aim was to correlate Topo I levels to pharmacokinetics and toxicity. Topo I levels were determined using Western blotting and were expressed relative to the Topo I level present in 10 microg cell lysate of the human IGROV1 ovarian cancer cell line. We found no correlation between Topo I levels and (non-)hematological toxicity. Topo I levels after the fifth topotecan infusion were significantly negatively correlated with the AUC of topotecan (R = -0.64, p = 0.026), in contrast with Topo I levels prior to (R = -0.25, p = 0.4) and after (R = -0.30, p = 0.3) the first topotecan infusion. Topo I levels after the fifth topotecan infusion (48 +/- 27%, mean +/- SD) were higher than Topo I levels prior to and after the first topotecan infusion (3.0 +/- 4.7 and 2.7 +/- 3.6%, respectively) (p = 0.001). In conclusion, we detected a significant inverse correlation between Topo I level and topotecan AUC at day 5, and we found increasing Topo I levels during a daily x 5 schedule of treatment with topotecan.