Aneri Penttilä

Pharmacokinetics of intravenously administered bumetanide in man

Disposition of [14C] bumetanide administered intravenously to four healthy volunteers could be described by a triexponential equation. The mean half-lives associated with each exponent were 5.9 min, 46 min, and 3.1 hr, respectively. The largest fraction of dose was eliminated during the second phase; only 17% was eliminated during the last phase. The total plasma clearance averaged 228 ml/min, with renal clearance about one-half of this value. The recovery of unchanged bumetanide in urine over 2 days was 47% of the dose, while the total recovery of radioactivity in urine averaged 82% of dose. In plasma 93% of bumetanide was bound to proteins. Thus bumetanide is rapidly eliminated by both renal and nonrenal mechanisms. The elimination kinetics resembled those described for furosemide.

The chemistry of dryopteris acylphloroglucinols

The ancient remedies effective against helminthiasis caused by fish tape worm, Diphyllobothrium latum, include the powdered rhizomes and extracts of dryopteris ferns which have had, and still have, a widespread use among the parasite infested populations. Extensive investigations in this field were started around the turn of the century by Boehm (1897, 1898, 1901a,b, 1903a-d) and resulted in the isolation of several dryopteris fern constituents as well as the resolution of the chemical structure of some of them. These studies have served as a basis for the current knowledge of the chemistry of dryopteris acylphloroglucinols. The basic chemical structure of the dryopteris constituents may be presented as a two-ring construction in which a butyrylfilicinic acid moiety (A-ring) is linked either to another similar moiety or to a Cor 0-methylated butyrylphloroglucinol moiety (B-ring), by means of a methylene bridge. Naturally occurring variations of this basic pattern include substitutions of the A-ring by an acylphloroglucinolic nucleus, enlargement of the molecule by additional acylphloroglucinol units to yield trimer or tetramer structures, substitution of the butyryl side-chain by an acetyl or propionyl homologue, and insertion of a pyrone ring structure instead of a phloroglucinolic one.

Paper chromatographic separation of the phloroglucinol derivatives from Dryopteris species.

A paper chromatographic technique, using buffered filter papers, is described for separating from Dryopteris ferns the phloroglucinol derivatives and some of their decomposition products. The RF values on papers buffered from pH 4.0 to pH 9.1 are given in the form of diagrams with the aid of which the appropriate buffer can be chosen depending on the mixture to be separated

Bumetanide kinetics in renal failure

To study the effects of renal failure on bumetanide kinetics, we administered single intravenous doses of 1.0 mg/3.08 μCi 14C‐bumetanide to six healthy subjects and 22 patients with variable degrees of renal failure. The kinetics of 14C‐bumetanide and total 14C were adequately described by a two‐compartment open model in the control subjects and in the patients. The volume of the central compartment and the distribution t½ were of the same order in both groups, whereas the mean (± SE) volume at steady state was larger (22.1 ± 1.6 and 16.9 ± 1.0 L) and the elimination t½ was longer (1.9 ± 0.2 and 1.4 ± 0.1 hours) in patients with renal failure than in healthy controls. Bumetanide renal clearance was lower (10 ± 3 and 90 ± 13 ml/min) in patients than in subjects and correlated with creatinine clearance (r = 0.784) and log serum creatinine level (r = −0.843), whereas nonrenal clearance was significantly higher in the patients (153 ± 14 and 99 ± 6 ml/min). Bumetanide total plasma clearance did not significantly change. The non—protein‐bound, free fraction of bumetanide was higher in patients and correlated with plasma albumin levels (r = −0.777). The kinetics of total 14C showed similar but greater changes than those of 14C‐bumetanide. Thus the most important changes in bumetanide kinetics in patients with renal failure are low renal clearance and a high free fraction, with a consequent increase in nonrenal clearance, volume of distribution, and elimination t½.

Human metabolism of tolfenamic acid. II. Structure of metabolites and C-13 NMR assignments of fenamates

SummaryMetabolites of tolfenamic acid appearing in human urine have been isolated and their structures determined by C-13 nuclear magnetic resonance and gas chromatography-mass spectrometry. Comparative studies on tolfenamic, mefenamic, and flufenamic acids in conjunction with the metabolites have permitted complete C-13 NMR assignments for this series of compounds. Five metabolites identified included three that were monohydroxylated, one that was both methoxylated and hydroxylated, and another in which the methyl group was oxidized to a carboxyl group. The information presented on the fenamate standards and the metabolites represents an excellent basis for structural elucidation of other fenamates and their metabolites.

Intestinal absorption, intestinal distribution, and excretion of [14C] labelled hyoscine N-butyl bromide (butylscopolamine) in the rat

Butylscopolamine was labelled with 14C and its gastrointestinal absorption, biliary and urinary excretion, enterohepatic circulation and gastrointestinal distribution were examined in anaesthetized rats. Biliary excretion was the main elimination route of intra‐portally administered [14C]butylscopolamine, with 42% of the dose recovered in the bile during 12 h. About 6% of the radioactivity administered orally as [14C]butylscopolamine was excreted in the bile and 1.2 % in the urine during 24 h, which indicates poor gastrointestinal absorption of butylscopolamine in the rat. When collected radioactive bile was readministered intrajejunally, only about 7% of the radioactivity was recovered in bile and urine during 12 h, which suggests that only a small fraction of butylscopolamine and its metabolites engage in an enterohepatic circulation. After oral administration of [14C]butylscopolamine, radioactivity was found to accumulate in the wall of the distal small intestine, and about 20% of the dose was found in this tissue 24 h after drug administration. As a result, local anti‐acetylcholine effects of butylscopolamine might be expected.

The absorption and elimination of orally administered [14C]hyoscine N-butylbromide (butylscopolamine)

The absorption of quaternary ammonium antiacetylcholine agents from the gastrointestinal tract has been much debated (Moller & Rosin, 1968 ; Hellstrom, RosCn & Soderlund, 1970; Beermann, Hellstrom & Rosin, 1971, 1972) and hyoscine N-butylbromide (butylscopolamine) has roused particular interest. While many authors hold that its absorption from the gut is insignificant (Herxheimer & Haefeli, 1966; Guignard, Herxheimer & Greenwood, 1968 ; Bromster, Carlberger & others, 1969 ; Hellstrom & others, 1970), its use clinically, even by mouth, has been found helpful in the treatment of various gastrointestinal disorders (Schmid, Bleichert & others, 1969). In animal studies with the labelled drug an enterohepatic circulation was proved (Pentikainen, Penttila & others, 1973). It has been suggested that after oral administration, though only absorbed slightly, it accumulates in the intestinal wall and the bile, and thus has a local effect (Pomeroy & Rand, 1968). This suggestion is supported by our animal results (Pentikainen & others, 1973). To throw more light on this question, the labelled drug has been given to two patients and the radioactivities of serum, bile and urine measured. [14C]Hyoscine butylbromide was synthesized (Pentikainen & others, 1973). Two volunteer female patients with normal liver function, aged 24 and 46 years and weighing 54 and 60 kg, had a T-drain, kept under a constant suction by a pressure of 50 mm of water (see Kaltiala, Penttila & others, 1974), inserted into the common bile duct after choledocholithotomy. On the morning after the operation one 10mg tablet of the drug, containing 17.1 pCi 14C, was taken with a glass of water on an empty stomach. Blood samples were taken from the cubital vein 20, 40, 60 and 180 minutes later