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Genetically determined differences in the ability of individuals to oxidize certain drugs by hepatic P-450 processes has gained increasing attention. The so-called debrisoquin hydroxylase, which is defective in approximately 5-10% of whites, is known to be of major importance for the metabolism of several drugs. The possible relation of this isozyme to the metabolism of narcotics eliminated by oxidative biotransformation has not been studied. Several narcotics were screened for in vitro interaction with this P-450 isozyme. This was accomplished by testing for competitive inhibition by narcotics of the 2-hydroxylation of desmethylimipramine in a human liver microsomal preparation. Alfentanil, fentanyl, and dextropropoxyphene were found to competitively inhibit this pathway demonstrating an interaction with this polymorphic isozyme. No interaction was found for codeine, meperidine, methadone, morphine, or nalbuphine. These results suggest that a genetic defect may be important for elimination clearance by metabolism for dextropropoxyphene, alfentanil, and fentanyl and that in vivo investigation is warranted.

The action of metformin with respect to in vitro turbidimetric clarification of a glyceridic system (lipostrate) has been studied in a group of metabolically healthy subjects. It is observed that biguanide associated with 3GS, heparinoid with known structure and costant liposemec activity, significantly accentuates clarifying activity whereas biguanide alone leads to only a slight increase in the clarification index, at least 5 times less than that induced by 3GS. Results are discussed. These agree with some recent experiments on the catabolic and antiatherogenic effect in vivo of biguanide on the VLDL and LDL, fostering their conversion into high density lipoproteins.

Urinary excretion of desipramine (DMI) and 2-hydroxydesipramine (2-OH-DMI) after single oral doses of 25 mg DMI was investigated in seven rapid and three slow debrisoquin hydroxylators, before and after pretreatment with either quinidine or its diastereoisomer quinine. After treatment with 800 mg quinidine daily for 2 days, excretion of 2-OH-DMI decreased by 96% in rapid hydroxylators and 68% in slow hydroxylators. After treatment with 750 mg quinine/day for 2 days, excretion of 2-OH-DMI in rapid hydroxylators was 54% lower than during the control experiment, whereas in slow hydroxylators no significant changes in the excretion pattern were observed. Unchanged DMI constituted only a minor fraction of recovered drug and no significant changes in its recovery were observed in either phenotypic group after pretreatment with quinidine or quinine. Thus both quinidine and quinine decreased the excretion of 2-OH-DMI. At similar does the effect of quinidine was much stronger than that of quinine, virtually transforming rapid hydroxylators into slow hydroxylators. The mechanism probably involves a stereoselective inhibition of DMI 2-hydroxylation.

The kinetics of an enteric-coated formulation of carbamazepine-10,11-epoxide (CBZ-E) were studied in healthy subjects. A single oral dose of 100 mg of CBZ-E was given to eight subjects. Four of them were also given a single oral dose of 200 mg of CBZ-E. Plasma concentrations of CBZ-E and urinary excretion of the end metabolite trans-10,11-dihydroxy-10,11-dihydro-carbamazepine (trans-CBZ-diol) were determined by high performance liquid chromatography. Plasma kinetics of CBZ-E fitted an open one-compartment model with plasma elimination half-life of 7.4 +/- 1.8 h (mean +/- SD). The clearance was 105 +/- 17 ml/kg/h and the apparent volume of distribution 1.1 +/- 0.2 L/kg assuming complete bioavailability. There was no indication of dose-dependent elimination of CBZ-E. The recovery of trans-CBZ-diol in urine collected for 3 days was 67 +/- 9% of the given dose. This enteric-coated formulation may thus in the future be used for the evaluation of the clinical effects of CBZ-E in patients.

Debrisoquine and S-mephenytoin hydroxylation phenotyping tests were performed in 9 patients before and during treatment with diazepam at a daily dose of 10 or 15 mg. There was no change in either the debrisoquine/4-hydroxydebrisoquine ratio or the ratio of S/R mephenytoin in urine. The hydroxylation of these two test drugs is apparently not inhibited by administration of therapeutic doses of diazepam.

A new homogeneous enzyme immunoassay technique (EMIT) for the measurement of plasma levels of amitriptyline, nortriptyline, imipramine, and desipramine was used with an automated procedure and the results were compared to those of a high-performance liquid chromatographic (HPLC) method. Precision of the EMIT test was similar to that of the HPLC method with within-day coefficients of variation in the range of 3.9-10.9% (EMIT) and 3.9-9.6% (HPLC). The day-to-day coefficients of variation ranged from 4.4 to 11.7% for EMIT and from 6.1 to 8.4% for HPLC. Samples from 124 patients were analyzed by both methods and a good correlation was observed for all the four drugs. A paired t test indicated no significant difference for the EMIT and HPLC values. No significant interferences were observed between the tricyclics tested and other commonly associated drugs, such as benzodiazepines and neuroleptics. The new EMIT assay proved to be rapid and easy to perform and showed sufficient reliability and reproducibility to be used for either emergency or routine analysis.

The rate of formation of 2-hydroxydesmethylimipramine was studied in microsomes from four human foetal and adult livers. The concentrations of desmethylimipramine ranged between 5 and 100 microM. The concentration of 2-hydroxydesmethylimipramine was measured by high pressure liquid chromatography with fluorescence detection. The kinetic parameters (Vmax and Km) were measured by Eadie-Hofstee plot. The Vmax (mean +/- S.E.M.) was 2.80 +/- 0.84 (foetal liver) and 73.1 +/- 11.6 (adult liver) pmol X min.-1 X mg-1. The corresponding values for Km (microM) were 36.3 +/- 6.5 (foetal liver) and 14.1 +/- 1.3 (adult liver). Both parameters were significantly different in foetal and in adult liver. The inhibitory effects of thioridazine, metoprolol, carbamazepine and cimetidine on the 2-hydroxylation of desmethylimipramine were studied in the foetal liver microsomes. Thioridazine and carbamazepine were the most powerful inhibitors.

The authors evaluated the clinical effectiveness and tolerability of doxofylline, a new methyl-xanthinic derivative with peculiar pharmacodynamic properties. 13 patients affected with chronic obstructive lung disease (mean age +/- 54 years) were studied. Doxofylline (200 mg) and theophylline (240 mg) were randomly administered by intravenous route in 60'. Arterial haemogasanalysis, FEV1 and ECG data were obtained after the infusion. Doxofylline proved to possess an equal therapeutic efficacy in comparison to theophylline, with a better clinical tolerability. In conclusion, doxofylline is a new and effective drug for the treatment of bronchostructive disorders.