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A nomogram is presented for modifying dosage regimens of drugs administered to patients with chronic renal function impairment. The usefulness and limitations of the nomogram are discussed in terms of the objectives of dosage regimens. The nomogram is intended to serve as a guide for drug administration in patients with renal disease. It may be particularly helpful for drugs on which little or no definitive research has been undertaken.

Rates of decay of semiquinones of certain derivatives of phenothiazine were measured in aqueous acetic acid solution using electron spin resonance spectroscopy and visible absorption spectrophotometry. Like that of phenothiazine itself, the semiquinones of the derivatives decayed by a second-order process with a rate constant inversely proportional to acid concentration. The rate results were consistent with a mechanism for the decay process as follows. Semiquinone undergoes rapid one-electron disproportionation by oxidation and reduction. The product of the oxidation (analog of phenazothionium ion) is unstable and is involved in two competing reactions. One is hydrolysis to sulfoxide, which is completely reversible to addition of acid. The other is a two-electron disproportionation producing the corresponding 3-hydroxyphenothiazine. In derivatives substituted on the nitrogen, the 3-hydroxy substitution is highly inhibited. The decay rates of the 3-substituted derivatives obey a Hammett relationship using para -substituent constants, while the 2,10-substituted derivatives obey a Hammett relationship using meta -substituent constants. An interesting relationship involving midpoint electrode potentials upon oxidation of certain 3-substituted phenothiazine derivatives is demonstrated.

Methotrexate (4-amino-AM°-methylpteroylglutamic acid) has been reported to be extensively metabolized by intestinal bacteria of mice and rats (1, 2) and to a lesser degree in man (3). Valerino (4) reported the separation of four different metabolites in the urine and feces of rats receiving tritiated methotrexate by gastric intubation and tentatively identified two as 2,4-diamino-6-carboxylpteridine and 2,4-diamino-6- methylpteridine. Although metabolites of methotrexate have been demonstrated in the urine and feces of animals, no reports of the separation of methotrexate from its metabolites in the plasma have appeared. A method for separation of methotrexate from its metabolites in plasma is essential for the necessary refinement of recently reported models of methotrexate pharmacokinetics (3, 5). These models have been derived from measurements of plasma concentrations of total radioactivity following administration of 3H-methotrexate. This communication reports a simple method for the separation of 8H-methotrexate from other labeled components in rat plasma.

Three spin labels were used to monitor possible drug- induced conformational changes in bovine serum albumin. The electron spin resonance spectra of labeled bovine serum albumin in all cases consisted of two subspectra corresponding to labels in a partially immobilized environment and a strongly immobilized environment. Only bovine serum albumin with the triazine spin label was suitable for quantitation of data. The strongly protein- bound acidic drug, phenylbutazone, caused a conversion of strongly immobilized sites to partially immobilized sites, an effect that was proportional to the amount of drug added. This probably was due to the initial drug binding inducing a conformational change in the bovine serum albumin, thereby exposing additional binding sites.