The disposition of feprazone and its hydroxylated metabolite in human volunteers

Abstract

1. ¹⁴C-Feprazone administered as a single oral dose (17 mg/subject) to each of 3 human volunteers on the 6th day of repeated dosage with unlabelled feprazone (200 mg/subject, twice daily) was excreted slowly, with only 19-38% of the dose excreted in the urine in 8 days, with a further 27-49% of the dose in the faeces.

2. ¹⁴C-Feprazone had a half-life of 30-33 h, similar to that after single dosage of unlabelled feprazone (22-33 h). The half-life for total ¹⁴C was not significantly different from that for unchanged feprazone, indicating that no metabolite with a very long half-life was formed.

3. Only feprazone and 4′-hydroxyfeprazone were detected in the plasma of subjects dosed orally with feprazone, the metabolite being characterized by mass spectrometry. The time of peak plasma concentration of feprazone was 4-5 h after dosage, and of 4′-hydroxyfeprazone was approx. 25 h. The urine contained feprazone plus its C-glucuronide, and 4′-hydroxyfeprazone plus its conjugate (glucuronide), in the ratio of approx. 5:1.

4. When 4′-hydroxyfeprazone was administered as a single oral dose to a human volunteer the plasma elimination half-life of the metabolite was 18 h, but after administration of feprazone the half-life of 4′-hydroxyfeprazone was 45 ± 29h (10 subjects), indicating the slow hydroxylation of feprazone and the slow excretion of 4′-hydroxyfeprazone. The clearance of feprazone was 5˙2 and of 4′-hydroxyfeprazone was 5˙5 ml/kg h.

5. These studies have shown that even though enterohepatic recirculation of the drug in man is indicated, the plasma half-life of feprazone is unchanged on repeated dosage, and accumulation of the drug at a daily dosage of 2 × 200 mg, does not occur.