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ABSTRACT:DB289 (pafuramidine maleate; 2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) is a prodrug of DB75 (furamidine dihydrochloride; 2,5-bis(4-guanylphenyl)furan dihydrochloride), an aromatic dication related to pentamidine that has demonstrated good efficacy against African trypanosomiasis, Pneumocystis carinii pneumonia, and malaria, but lacks adequate oral availability. The pharmacokinetics and metabolism of 14 C-DB289 have been investigated in rat and monkey after oral and intravenous administration. Oral doses were well absorbed (ϳ50-70%) and effectively converted to DB75 in both species but subject to first-pass metabolism and hepatic retention, limiting its systemic bioavailability to 10 to 20%. Clearance of DB289 approximated the liver plasma flow and its large volume of distribution was consistent with extensive tissue binding. Plasma protein binding of DB289 was 97 to 99% in four animal species and humans, but that of DB75 was noticeably less and more species-and concentration-dependent. Together, prodrug and active metabolite accounted for less than 20% of the plasma radioactivity after an oral dose, but DB75 was the major radiochemical component in key organs such as brain and liver and was largely responsible for the persistence of 14 C in the body. The predominant route of excretion of radioactivity was via the feces, although biliary secretion was not particularly extensive. High-performance liquid chromatography and liquid chromatography-mass spectrometry investigations showed that the formation of DB75 from the prodrug involved the sequential loss of the two N-methoxy groups, either directly or by O-demethylation followed by reduction of the resulting oxime to the amidine. It was estimated that almost half of an oral dose of DB289 to rats and about one-third of that to monkeys was metabolized to DB75.

Summarg1. The dose-response relationship between the oral anticoagulant, warfarin, and its effect on the metabolism of phylloquinone (vitamin K,) has been examined in normal male volunteer subjects.2. In each study the subject received a single, oral dose of warfarin and, 2 h later, an intravenous injection of [l ',2'-3H2 Jphylloquinone. Changes in the metabolism of phylloquinone were assessed by thefractionation and chromatographic separation of labelled phylloquinone and its metabolites in plasma and urine samples.3. Increasing doses of warfarin did not affect the rate of disappearance of injected phylloquinone from the plasma but caused the accumulation of increasing amounts of the metabolite, phylloquinone epoxide.4. Increasing doses of warfarin were found to decrease the proportion of labelled conjugates excreted in the urine as glucuronides and to block progressively the excretion of the normal aglycones of phylloquinone. At the same time there was a progressive increase in the excre tion of at least three abnormal aglycones of phylloquinone. 5. The doses or plasma concentrations of warfarin were related to the increase in phylloquinone epoxide in the plasma and to the decrease in the proportion of normal aglycones of phylloquinone in urine by typical log doseCamspondence: Dr M. J. Shearer, Department of Hacmatology, Clinical Science Laboratories, Tower Block, Guy's Hospital, London SEl 9RT.response curves, which were linear over the therapeutic range.6. The nature of the metabolites detected suggested that the dose-response curves reflected the progressive inhibition by warfarin of the enzyme, phylloquinone epoxide reductase. 7.The results are consistent with the hypothesis that the pharmacological action of oral anticoagulants is closely linked to their ability to inhibit the cyclic interconversion of vitamin K and vitamin K epoxide.

In normal healthy subjects radiographic contrast media are cleared by the kidneys with a half-life of approximately 2 h and a total body clearance of 8 l/h. The mechanism of contrast clearance has not been previously investigated in chronic renal failure patients undergoing continuous ambulatory peritoneal dialysis (CAPD). A study was undertaken to investigate the pharmacokinetics of a non-ionic water soluble radiographic contrast medium (iopamidol) in 10 patients stabilized on CAPD. All patients (eight male, two female) aged 22-68 years (median 53 years) had injection of 30 ml of iopamidol 300 via a forearm vein to investigate subclavian vein patency following previous cannulation for haemodialysis. Venous blood samples, CAPD dialysate and urine were collected for seven days post injection. The mean plasma half-life was 37.9 h (SD 10.6) (range 24.1-57.2 h) for the CAPD patients and was greatly prolonged in comparison to healthy subjects. The total body clearance of iopamidol was also greatly reduced (0.377 l/h). CAPD removed an average of 53.6% of the administered dose (range 36.3-80.8%) whilst an average of 26.9% was excreted in the urine (range 1.3-56.3%). The combined renal and dialysate clearance was up to 93% of the administered dose over the period of the study. There is therefore some evidence for a small extra renal clearance of iopamidol in end-stage renal failure patients. This study has shown for the first time that patients with end-stage renal failure undergoing CAPD have significantly delayed elimination of contrast medium. This should be taken into consideration when extensive or prolonged investigations using contrast medium are proposed.