The pharmacokinetics and beta-adrenoceptor blocking effects of conventional and sustained-release metipranolol have been studied in 6 healthy male volunteers given a single oral dose of 40 mg. Plasma drug concentrations determined by TLC and a radioreceptor assay, and the inhibition of exercise-induced tachycardia, were monitored for 48 h. Relevant amounts of active metabolites other than deacetylmetipranolol were not found. Compared to conventionally formulated metipranolol, the controlled-release product had a prolonged mean residence time (10.7 vs 5.5 h), the peak drug concentration was halved and the time to peak drug concentrations was delayed. Relatively constant plasma concentrations (cideal = 6.5 ng/ml) and a clinically significant reduction of exercise-induced tachycardia were maintained throughout a 24 h dosing interval. An individual deacetylmetipranolol plasma concentration-effect relationship was evaluated using the Emax model. Mean parameters were Emax 26% and C50 2.9 ng/ml.
Based on pharmacokinetic data from mice, rats, and rabbits, the prediction of pharmacokinetics of intravenous metazosin in man has been performed. The correlations were based upon allometric scaling of plasma clearance and the volume of distribution at steady-state. A one-compartment body model approximating clinical pharmacokinetics fits well the elimination phase of subsequently measured metazosin concentrations in volunteers. Fitting human pharmacokinetic data to allometric equations enabled us to superimpose pharmacokinetic curves from different species.
We prepared mutants of Streptomyces cinnamonensis resistant to amino acid analogues: 2‐aminobutyrate, norvaline, norleucine, 2‐amino‐3‐chlorobutyrate and ethionine. The regulatory mutants were studied as to their production of oligoketide antibiotics, monensins A and B, as dependent on the formation of valine which is a precursor of the butyrate building unit of monensin A. Strains resistant to both 2‐amino‐3‐chlorobutyrate and norleucine exhibited an increased production of monensin A from 50% to 90–93% of total monensins.
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