Expression of lung-resistance protein gene is not associated with platinum drug exposure in lung cancer.

BACKGROUND: Platinum drug resistance is an important problem in lung cancer chemotherapy. In this study, we examined lung-resistance protein (LRP) gene expression in vivo and in vitro in relation to platinum drug exposure. MATERIALS AND METHODS: The expression levels of the LRP gene were assessed by the reverse transcription polymerase chain reaction, in 80 autopsy samples (40 lung tumors and 40 corresponding normal lung tissues), two lung cancer cell lines and in peripheral mononuclear cells collected from 8 lung cancer patients before and after platinum drug administration. RESULTS: The LRP gene expression levels of autopsy specimens exposed antemortem to platinum drugs were not significantly different to those of specimens without platinum drug exposure, for both lung tumors and normal lung tissues. Our results also demonstrate that LRP gene expression was not induced by platinum drugs either in vitro or in vivo. CONCLUSIONS: The present results indicate that LRP gene expression is not associated with platinum drug exposure in lung cancer.

Limited-sampling models for estimation of the carboplatin area under the curve.

BACKGROUND: The area under the curve (AUC) of free carboplatin, is a major determinant of toxicity and response. A conventional pharmacokinetic study to determine AUC requires frequent blood sampling. One strategy for overcoming this problem is to apply a limited sampling model (LSM). MATERIALS AND METHODS: We developed LSMs by stepwise forward multiple regression analysis using 27 data series from 24 patients with lung cancer (training data set) who received carboplatin in combination with oral etoposide. The models were then validated using 24 data series from 18 patients (test data set). RESULTS: In the test data set, the single-sample model was confirmed to give excellent estimation of the AUC: AUC (mg/ml x min) = 0.93 x C3h + 0.47 (MPE% = 4.4%, RMSE% = 8.9%). Furthermore, the two-sample model was shown to improve both the bias and precision of AUC estimation: AUC = 0.16 x C1h + 2.26 x C8h + 0.75 (MPE% = 0.9%, RMSE% = 5.3%). CONCLUSIONS: Our models are useful for future trials to define the accurate relationships between the dose-intensity and effect of carboplatin.

Inhibition of theophylline metabolism by aciclovir.

We report a case of side effects caused by the increase in plasma theophylline concentration after coadministration of aciclovir had been started during theophylline therapy. Interaction between theophylline and aciclovir has not previously been reported. Therefore, a study of the pharmacokinetic and metabolic interactions between theophylline and aciclovir was carried out in five healthy male volunteers. All subjects received a single oral dose of 320 mg theophylline (aminophylline, 400 mg) after they had taken oral aciclovir 800 mg five times daily for two consecutive days. The area under the curve from 0 to infinity of theophylline (AUC0-infinity) after coadministration of aciclovir was increased from 189.9 +/- 18.2 to 274.9 +/- 34.3 micrograms.h/ml (p < 0.01), and total body clearance was decreased from 28.4 +/- 2.9 to 19.8 +/- 2.5 ml/h/kg (p < 0.01). Further, there was a significant increase in urinary theophylline and decreases in urinary 1,3-dimethyluric acid and 1-methyluric acid after coadministration of aciclovir. The decrease in total body clearance is likely to have resulted from inhibition of metabolism via the oxidation pathway. The results indicated that with aciclovir therapy lower doses of theophylline might be necessary and careful monitoring of plasma concentrations was essential.

Bioavailability of 50- and 75-mg oral etoposide in lung cancer patients.

This study was designed to determine the bioavailability of etoposide capsules administered orally at doses of 50 and 75 mg. Patients with inoperable or relapsed lung cancer, who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function, were eligible. A group of 17 patients were evaluable, all of whom were 75 years old or less, with an ECOG performance status of 0 or 1. The bioavailability of oral etoposide was determined by measuring the area under the etoposide plasma concentration versus time curve (AUC) on days 1, 10 and 21 during a once-daily regimen of oral administration for 21 consecutive days and comparing the value with the AUC achieved following intravenous administration 1 or 2 weeks after the last oral dose. The bioavailability of 50, 75 and 100 mg oral etoposide was determined in six, nine and two patients, respectively. The mean etoposide bioavailabilities (+/- SD) of the 50-mg and 75-mg doses were 47 +/- 11% and 59 +/- 18%, respectively, and of the 100-mg dose in two patients were 51% and 33%, respectively. There was no statistically significant difference in bioavailability between the 50-mg and 75-mg doses. The bioavailability of low-dose oral etoposide was the same as that reported in previous higher dose oral etoposide bioavailability studies and that shown on the package insert supplied by the manufacturer. Improved bioavailability of low-dose oral etoposide was therefore not observed in a population of Japanese patients.

High-performance liquid chromatographic determination of irinotecan (CPT-11) and its active metabolite (SN-38) in human plasma.

A simplified method for the simultaneous determination of irinotecan (CPT-11, I) and its active metabolite (SN-38, II) in human plasma by high-performance liquid chromatography (HPLC) with fluorescence detection has been developed. Following the addition of the internal standard (I.S.) camptothecin, the drugs were extracted from plasma using methanol. The average extraction efficiencies were 87% for I, 90% for II and 90% for the I.S. Chromatography was performed using a TSK gel ODS-80Ts column, monitored at 556 nm (excitation wavelength, 380 nm) and the mobile phase was acetonitrile-50 mM disodium hydrogen phosphate (28:72) containing 5 mM heptanesulphonate (pH 3.0). The linear quantitation ranges for I and II were 30-2000 and 1-30 ng/ml, respectively.

Phase I study and clinical pharmacological evaluation of daily oral etoposide combined with carboplatin in patients with lung cancer.

Twenty-eight patients with inoperable or relapsed lung cancer were given a combination of oral etoposide, administered once a day at doses ranging from 40 to 60 mg/m2/day (d) for 21 consecutive days, and carboplatin, administered intravenously over 1 h at doses ranging from 300 to 400 mg/m2 on day 1 to determine the appropriate doses of this combination. In addition, pharmacokinetic and pharmacodynamic analyses were performed. All the patients had a performance status of 0 to 1. Serum etoposide and free platinum (Pt) concentrations were measured using high-performance liquid chromatography and atomic absorption, respectively. Myelosuppression, nausea and vomiting were the dose-limiting toxicities of this schedule. The maximum tolerated dose (MTD) was 50 mg/m2/d oral etoposide for 21 days and 400 mg/m2 i.v. carboplatin on day 1. For heavily pretreated patients, the MTD was 40 mg/m2/d oral etoposide for 21 days and 350 mg/m2 i.v. carboplatin on day 1. No cumulative increase in the area under the concentration-time curve (AUC) for oral etoposide over time was observed. There were significant correlations between the free Pt serum level (6, 8, 12, 24 h post-dose) and etoposide AUC level (days 1, 10 and 21) for graded hematological toxicity, and the percentage decreases and nadir counts of hemoglobin, leukocytes, neutrophils and platelets. Several pharmacodynamic models were developed to predict the hematological toxicity. In order to facilitate pharmacodynamic evaluations in future studies, a limited sampling model for oral etoposide was also developed and validated.