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The distribution into cerebrospinal fluid (CSF) of five 3H- or 14C-labelled beta-adrenoceptor blocking drugs given intravenously was studied in urethane-anaesthetized rats. The doses (mg/kg) were: alprenolol 5, metoprolol 1, oxprenolol 5, pindolol 0.5, propranolol 0.1 and 5. Within 15 min. a marked fraction of the given radioactivity appeared in CSF with all substances. During the follow-up period of 315 min., only propranolol, independently of dose, caused high CSF/plasma ratios (0.54-0.73) of radioactivity. The other four beta-adrenoceptor blocking drugs caused levels of CSF radioactivity which were 0.05-0.28 of that in plasma and 0.05-0.14 of the calculated levels of activity in the whole body. Since propranolol is bound to plasma proteins to a higher degree than the other drugs studied, the penetration of the unbound fraction of propranolol into rat CSF is even more pronounced than what would be expected on the basis of CSF/plasma ratio measured.

The metabolic fate and pharmacokinetics of tolfenamic acid, a new anti-inflammatory agent, was studied after intravenous and oral administration of14C-tolfenamic acid to one healthy volunteer. The recovery in urine was 77% of the intravenous dose and 93% of the oral dose. About 11% of the doses was found in faeces after both routes of administration whereas no radioactivity was detected in expired air, saliva or red cells. In plasma 90–99% of the radioactive compounds were bound to proteins whereasin vitro protein-binding of tolfenamic acid was 99.7%. Tolfenamic acid was biotransformed into several metabolites and only less than 10% of the doses was excreted into urine as the glucuronide/sulphate conjugate of unchanged drug. Tolfenamic acid and four metabolites were separated by TLC, together they accounted for 90–100% of urine radioactivity. Two major metabolites with preliminary identification as hydroxylation products of tolfenamic acid were isolated in pure form for further structural analysis. After fast initial decline the total plasma radioactivity decreased slowly with a mean half life of 58 hours. The elimination rate of tolfenamic acid into urine was fast with a half life of 1.9 hours whereas the metabolites were eliminated more slowly. Their elimination showed three phases, a rapid initial phase up to six hours, second phase up to 48 hours with half lives ranging from 9 to 13 hours and a third terminal slow, quantitatively minor, phase thereafter.

Metabolites 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.

To study the effects of renal failure on bumetanide kinetics, the authors administered single intravenous doses of 1.0 mg/3.08 microCi /sup 14/C-bumetanide to six healthy subjects and 22 patients with variable degrees of renal failure. The kinetics of /sup 14/C-bumetanide and total /sup 14/C 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 t1/2 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 t1/2 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 +/- /sup 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). Themore » kinetics of total /sup 14/C 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 t1/2.« less

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.

Glycopyrrolate was labelled in one methyl group with tritium and its fate was studied in six patients with T-tube drainage by determining serum levels as well as the biliary and urinary excretion of radioactivity after intravenous injection. More than 90 % of the radioactivity had disappeared from serum in 5 min and after 30 min almost no radioactivity could be found. The highest radioactivity in bile was found in samples taken 30 or 60 min after the injection. However, measurable radioactivity was found in most cases after 48 h. The first urine samples (0–3 h) showed the greatest radioactivity, and in 48 h 85% of the total radioactivity was excreted into the urine. Paper chromatography showed that both in bile and in urine over 80% of the radioactivity corresponded to unchanged glycopyrrolate. That appreciable amounts of glycopyrrolate were excreted into the bile suggests that the spasmolysis achieved with glycopyrrolate could be based partly on a local action on the bile ducts.

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.

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