Pharmacokinetic and pharmacodynamic interactions between diltiazem and quinidine.

OBJECTIVES: To examine the pharmacokinetic and pharmacodynamic interactions between quinidine and diltiazem because both drugs can inhibit drug metabolism. METHODS: Twelve fasting, healthy male volunteers (age, 24 +/- 5 years; weight, 75 +/- 10 kg) received a single oral dose of diltiazem (60 mg) or quinidine (200 mg), alone and on a background of the other drug, in a crossover study. Background treatment consisted of 100 mg quinidine twice a day or 90 mg sustained-release diltiazem twice a day for 2 day before the study day. RESULTS: Pretreatment with diltiazem significantly (p < 0.05) increased the area under the curve of quinidine from 7414 +/- 1965 to 11,213 +/- 2610 ng.hr/ml and increased its terminal elimination half-life (t1/2) from 6.8 +/- 1.1 to 9.3 +/- 1.5 hours. Its oral clearance was decreased from 0.39 +/- 0.1 to 0.25 +/- 0.1 L/hr/kg, whereas the maximal concentration was not significantly affected. Diltiazem disposition was not significantly affected by pretreatment with quinidine. Diltiazem pretreatment increased QTc and PR intervals and decreased heart rate and diastolic blood pressure. No significant pharmacodynamic differences were shown for diltiazem alone versus quinidine pretreatment. CONCLUSION: Diltiazem significantly decreased the clearance and increased the t1/2 of quinidine, but quinidine did not alter the kinetics of diltiazem with the dose used. No significant pharmacodynamic interaction was shown for the combination that would not be predicted from individual drug administration.

High-performance liquid chromatographic assay for sematilide in plasma using solid-phase extraction microcolumn technology.

A simple and sensitive high-performance liquid chromatographic assay for quantification of sematilide in rabbit plasma was developed. After extraction of samples via solid-phase extraction on C8 microcolumns, baseline resolution was achieved on a reversed-phase 5 microns Inertsil ODS-2 column using isocratic conditions with mobile phase consisting of water-glacial acetic acid-acetonitrile-methanol-triethylamine (93.5:4.0:1.5:0.5:0.5) and UV detection at 254 nm. The assay did not require evaporation or reconstitution steps. The injection interval was 8 minutes. The inter-day coefficient of variation for replicate analysis of spiked samples was less than 7.6% and the accuracy was more than 97% over the standard curve range (0.128 to 3.191 microM) using 0.5 ml of plasma. The assay has been successfully applied to pharmacokinetic studies in rabbits.

Amrinone and N-acetylamrinone assay in human plasma using solid-phase extraction and reversed-phase chromatography.

A simple and sensitive liquid chromatographic assay for simultaneous quantitation of amrinone and N-acetylamrinone in human plasma was developed. The method involves extraction of samples via activated solid-phase extraction Bond Elut C18 disposable columns, followed by chromatographic separation on a reversed-phase phenyl column using isocratic condition and UV detection. The assay can measure concentrations of both compounds over the range 0.075-10 micrograms ml-1. The injection interval is 11 min. The inter-day relative standard deviation (RSD) for replicate analysis of spiked samples is less than 10% and the accuracy more than 94% for both compounds over the standard curve range. The assay has been successfully applied to pharmacokinetic studies in humans.

A comparison of lumbar epidural and intravenous fentanyl infusions for post-thoracotomy analgesia.

This double-blind randomised study compared the analgesic efficacy, respiratory effects, side effects, and pharmacokinetic disposition of 24 hr lumbar epidural and intravenous infusions of the same dosage regimen of fentanyl (1.5 micrograms.kg-1 bolus then 1 microgram.kg-1.hr-1 infusion) in 50 patients after thoracotomy. Patients received either epidural fentanyl and intravenous normal saline, or epidural normal saline and intravenous fentanyl, for postoperative analgesia, after a standard low-dose alfentanil and isoflurane general anaesthetic. Visual analogue pain scores were lower in the epidural group (P < 0.05) only at two hours postoperatively, and there was no difference in the amount of supplementary morphine self-administered by patient-controlled analgesic pump. A mainly spinal analgesic effect probably occurred in the first few hours since fentanyl was not detectable in the plasma of patients in the epidural group until two hours after bolus injection; its concentration was less at that time than after intravenous injection (P < 0.05). Thereafter there was no difference in the plasma concentration profiles between the two groups. Seven patients in the epidural group and ten patients in the intravenous group received naloxone for PaCO2 > 50 mmHg, and one patient in the intravenous group had the infusions stopped because of PaCO2 elevation and somnolence. In patients who did not receive naloxone, the epidural route produced better analgesia throughout the study period (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)