Assessment of the potential for a pharmacokinetic interaction between fluoxetine and terfenadine.

OBJECTIVE: To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates. BACKGROUND: Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fluoxetine inhibits this metabolism as a model for CYP3A drug interactions. METHODS: Male subjects (n = 12) were given two single doses of 60 mg terfenadine alone (treatment 1) and again after the eighth dose in a 9-day regimen of 60 mg fluoxetine once a day (treatment 2). Blood samples, collected up to 48 hours after each terfenadine dose, were assayed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompartmental pharmacokinetic data for terfenadine and terfenadine acid metabolite were compared between treatments. RESULTS: Mean value +/- SD plasma concentrations of fluoxetine (165 +/- 45 ng/ml) and norfluoxetine (83 +/- 23 ng/ml) achieved after the eighth dose did not cause a significant change in terfenadine acid metabolite pharmacokinetics. All terfenadine concentrations were less than 5 ng/ml and they were approximately 30% lower after fluoxetine pretreatment compared with terfenadine alone. The area under the concentration-time curve for terfenadine was lower after fluoxetine administration, a statistically significant difference, but the peak concentration of terfenadine was not significantly different. Because most antihistaminic activity after terfenadine administration is attributed to its acid metabolite, the small decrease in terfenadine concentration is not clinically significant. No subject discontinued the drugs because of an adverse event. CONCLUSION: Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates.

Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers.

Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125I]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coefficients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids.

Effects of renal dysfunction on the pharmacokinetics of loracarbef.

Loracarbef, the first carbacephem antibiotic to undergo clinical development, is excreted primarily unchanged in the urine (> 90%). Data analyzed from subjects with various degrees of renal dysfunction who were given single oral doses of loracarbef indicated a linear relationship between creatinine clearance (CLCR) and plasma clearance [CLP (L/hr) = 0.106.CLCR (ml/min/1.73 m2)]. The mean area under the plasma concentration-time curve in normal subjects and in patients with severe renal insufficiency (no dialysis/receiving dialysis) was 32 micrograms.hr/ml and 1085 micrograms.hr/ml/103 micrograms.hr/ml, respectively. Therefore, for individuals with moderate renal insufficiency (CLCR, 10 to 49 ml/min/1.73 m2), the dose should be halved or the dosing interval doubled; patients with severe renal insufficiency who are not receiving dialysis should be treated with the normal dose given once every 3 to 5 days. Loracarbef is readily cleared from plasma by hemodialysis; dosing should be repeated after a hemodialysis treatment.

Disposition of zatosetron, a serotonin (5-HT3) receptor antagonist, in humans.

Zatosetron is being tested clinically as an antianxiety agent; it is a highly selective antagonist of the serotonin 5-HT3 receptor, with minimal agonist activity. The disposition of [14C]zatosetron was studied in five healthy men after a single oral dose (46.2 mg). Serum levels of radioactivity and parent drug peaked in 3-8 hr. About 15% more radioactivity was measured in red blood cells than in plasma. In serum, the parent compound represented about 85% of the radioactivity, zatosetron-N-oxide represented 10%, and N-desmethyl-zatosetron and 3-hydroxy-zatosetron each represented 2-3%. The t1/2 of zatosetron was 25-37 hr. About 75% of zatosetron added to human plasma became reversibly bound to protein. Concentrations of zatosetron in saliva were generally 10-50% higher than those in serum. About 80% of the administered radioactivity was eliminated in urine and 20% in feces; radioactivity was measurable in the excreta for 10-12 days after drug administration. The major route of metabolism of zatosetron was a stereoselective N-oxidation to form 8-alpha-methyl, 8-beta-oxo zatosetron (zatosetron N-oxide). In urine, approximately 45% of the radioactivity was unchanged zatosetron, 35% was zatosetron N-oxide, 10% was N-desmethyl-zatosetron, and 5% was 3-hydroxy-zatosetron. In feces, 30% of the radioactivity was unchanged zatosetron, and 70% was N-desmethyl-zatosetron. Overall, approximately 60% of the administered zatosetron was metabolized in humans. In a separate multiple-dose study, the disposition of zatosetron was found to be similar to that in the single-dose study.

Pharmacokinetics of cefaclor AF: effects of age, antacids and H2-receptor antagonists.

The pharmacokinetics and bioavailability of cefaclor advanced formulation (cefaclor AF) were investigated in two studies, one comparing healthy elderly and younger volunteers and the other assessing the effects of an antacid and H2-receptor antagonist on cefaclor AF bioavailability. The pharmacokinetics of a 750 mg dose of cefaclor AF were studied in 30 subjects ranging in age from 65 to 84 years and 10 control subjects 21-45 years of age. Compared with controls, elderly subjects exhibited higher plasma concentrations of cefaclor which were attributed to lower plasma clearance. There was a strong association between age and renal function, and the plasma clearance of cefaclor was highly dependent upon renal function. Thus, elderly patients with impaired renal function had a reduced ability to eliminate cefaclor. Due to a short elimination half-life and wide therapeutic index, dosage adjustments are not necessary in patients exhibiting moderate renal dysfunction. The 15 healthy men in the second trial were crossed over to receive five treatments, including cefaclor AF (500 mg) alone, cefaclor AF with or preceded by cimetidine, cefaclor AF followed by Maalox TC and cefaclor immediate release (500 mg) alone. Cefaclor AF and immediate release cefaclor had similar bioavailability, but plasma concentrations were maintained for a longer period of time when cefaclor AF was administered. Cimetidine did not alter the bioavailability of cefaclor AF but Maalox TC, coadministered with cefaclor AF, reduced the extent of absorption. This suggests that cefaclor AF bioavailability is influenced by the antacid Maalox TC but not by H2-receptor antagonist cimetidine.

Effect of probenecid on the pharmacokinetics of moxalactam.

The effects of probenecid on the pharmacokinetics of moxalactam were studied in normal volunteers administered a 2-min l-g intravenous infusion. The results showed that probenecid did not alter the plasma or urinary concentrations of moxalactam, its apparent volume of distribution, plasma elimination half-life, elimination rate constant, or plasma and renal clearances. Therefore, moxalactam appears to be eliminated primarily by the kidney via glomerular filtration.