Franz-Josef Leinweber

Possible physiological roles of carboxylic ester hydrolases.

(1987). Possible Physiological Roles of Carboxylic Ester Hydrolases. Drug Metabolism Reviews: Vol. 18, No. 4, pp. 379-439.

l-Bunolol Metabolites in Human Urine

Nine radiolabeled compounds were identified in human urine after administering a single oral dose of 3H-l-bunolol (3 mg) to 5 male volunteers. These compounds represented 54.7% of the dose and 71.4% of the isotope excreted in 3 days. Intact bunolol accounted for 14.7% of the dose and its conjugates totaled an additional 5.0%. The major drug metabolite (28.2% of dose) was dihydrobunolol, a reduction product known to have the same pharmacological activity and potency as bunolol. Dihydrobunolol conjugates amounted to 3.9% of the dose. Two minor acidic metabolites were produced by oxidative cleavage of the bunolol side chain, and another minor metabolite (hydroxydihydrobunolol) resulted from both reductive and oxidative biotransformation. Bunolol metabolism in man showed qualitative and quantitative differences from patterns observed in the rat and dog.

A New Oxisuran Metabolite

1. An unidentified oxisuran metabolite which had been observed in animal urine was biosynthesized by incubating [14C]oxisuran with rat liver cytosol. 2. The metabolite, isolated by preparative t.l.c. and extraction, was identified as oxisuran alcohol sulphide by mass fragmentography. Confirmation of this identification was obtained by biosynthesis of the same compound from oxisuran sulphide. 3. The 9000 g supernatant liquid from rat liver was less effective than cytosol in reducing oxisuran to its alcohol sulphide. Neither rat liver fraction reduced oxisuran alcohol sulphoxides to sulphide. 4. The 9000 g fraction oxidized oxisuran and oxisuran alcohol sulphoxide to oxisuran alcohol sulphone.

Metabolism of the anti-obesity agent, 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride, in rats and dogs

1. In 24 h, male rats excreted in urine 1% of an intra-gastric 100 mg/kg dose of 4-amino-5-ethyl-3-[4-14C]thiophenecarboxylic acid methyl ester hydrochloride (I) as unchanged I and 59% as 4-amino-5-ethyl-3-thiophenecarboxylic acid (II), mostly conjugated. 2. In rats dosed intra-duodenally with I (50 mg/kg), little I was found in the systemic circulation (less than 2 micrograms/ml) but high concentrations (26 micrograms/ml) were present at five minutes in portal plasma. At five minutes, II was found at 89 and 93 micrograms/ml in systemic and portal plasma, respectively. First-pass ester hydrolysis by the duodenum and liver may explain the near absence of I and the high concentrations of II in systemic plasma. 3. Dogs which received 30 mg/kg 14C-I intra-gastrically, excreted 0.3% I, 30.8% II and 6.8% as 5-ethyl-4-(methylamino)-3-thiophenecarboxylic acid (III), the N-methyl derivative of II. 4. Dogs which received approximately equivalent intra-venous or intra-gastric doses of non-radioactive I and II had high plasma concentrations of II but only small concentrations of I. Plasma concentrations of II after intra-gastric doses of non-radioactive I or II were similar, indicating that both compounds are pharmacokinetically equivalent. I may be a prodrug of II.

Pharmacodynamic studies with (−)-3-phenoxy-N-methylmorphinan in rats

Analgesia and brain and plasma concentrations of (-)-3-phenoxy-N-methylmorphinan (PMM) and its metabolites were determined in rats administered 50 mg/kg of 3H-labeled PMM p.o., an approximate ED50. Unchanged PMM and two active metabolites, levorphanol and a different phenol, p-hydroxylated on the 3-phenoxy group (pOH-PMM), were present in brain at concentrations greater than in plasma. Analgesia was observed from 1 to 6 hr and was associated with brain concentrations of 400-1400 ng/g of PMM, 190-300 ng/g of pOH-PMM, and 16-27 ng/g of levorphanol. The presence of 58% of the administered dose as unchanged PMM in the gastrointestinal tract at 6 hr may reflect slow absorption and explain the persisting brain concentrations of PMM and its metabolites as well as the prolonged analgesia. Analgesia may have been due to the presence in brain of only PMM, pOH-PMM or levorphanol, or to the combined activity of two or three of these substances. Administration of the approximate ED50 of 3H-labeled levorphanol (0.1 mg/kg, s.c., or 6 mg/kg, p.o.) resulted in brain levorphanol concentrations (11-18 ng/g) close to those observed when PMM was administered p.o. at 50 mg/kg. After administration of an approximate subcutaneous ED50 of [3H]pOH-PMM of 24 mg/kg, the brains contained pOH-PMM (1500-4100 ng/g) and levorphanol (60-100 ng/g); these levorphanol concentrations were higher than those found after administration of the approximate ED50 of PMM or levorphanol. The findings indicate that brain levorphanol concentrations resulting from administration of PMM or pOH-PMM to rats may account for the analgesic activity observed, i.e. that PMM and pOH-PMM may act as prodrugs for levorphanol

Bunolol Metabolism by Dogs: Urinary Excretion of 5-Hydroxytetralone

1. Anion exchange and t.l.c. were used to collect the polar drug metabolites present in urine of dogs treated orally with [14C]bunolol. 2. A new metabolite, 5-hydroxytetralone, was isolated, purified, and identified by u.v.,i.r. and mass spectroscopy. 3. 5-Hydroxytetralone represented 1.7% dose excreted in urine collected for 24 h after bunolol administration. 4. Properties of the metabolite are discussed in relation to the question of whether 5-hydroxytetralone was excreted as a conjugate.