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Biomedical subjects

E A Lane

Publications and source records attributed to E A Lane.

At least 37 records · Page 2Linked to original sources
PubMed1985

Fractions metabolized in a triangular metabolic system: cinromide and two metabolites in the rhesus monkey.

A previous study of the metabolic fate of cinromide (3-bromo-N-ethylcinnamamide) in rhesus monkey established that half of a dose is metabolized by N-deethylation to an active metabolite, 3-bromocinnamamide. Both cinromide and its proximal metabolite can be metabolized by amide hydrolysis to a second metabolite, 3-bromocinnamic acid, resulting in a triangular metabolic problem. This investigation was undertaken to distinguish between these two nonexclusive possibilites. A preliminary study was carried out to characterize the pharmacokinetics of 3-bromocinnamic acid. In the main study, six monkeys received an intravenous dose of cinromide, 3-bromocinnamamide, and 3-bromocinnamic acid in a randomized order. The time courses of compound administered and corresponding metabolites were followed. The following fractions of dose metabolized (mean +/- SD) were obtained: cinromide to 3-bromocinnamide: 0.53 +/- 0.24; 3-bromocinnamamide to 3-bromocinnamic acid: 0.53 +/- 0.21; cinromide to 3-bromocinnamic acid directly: 0.48 +/- 0.32. Thus, it was found that 3-bromocinnamic acid is formed directly from cinromide and from 3-bromocinnamamide. Also, as primary metabolites, 3-bromocinnamic acid and 3-bromocinamamide account for all of a cinromide dose with a mean value of 1.00 +/- 0.34. The observed variability in these fractions metabolized was explained by the fact that in the solution of the triangular metabolic problem, three clearances are assumed to remain constant over three studies.

Animals↗
PubMed1985

Interethnic dissociation between debrisoquine and desipramine hydroxylation.

Chinese and Caucasian volunteers who had previously participated in a single dose desipramine pharmacokinetic study underwent debrisoquine hydroxylation phenotyping. After a single 10-mg oral dose of debrisoquine, urinary concentrations of the drug and its major metabolite, 4-hydroxy-debrisoquine (4-OHD), from an 8-hour collection were more variable in the Caucasians. Compared to the Chinese, the Caucasian subjects tended to excrete higher mean fractions of the dose as unchanged debrisoquine (10.9 +/- 8.8% vs. 6.3 +/- 2.6%) and 4-OHD (15.9 +/- 13.0% vs. 9.7 +/- 7.7%), although given the high variability the differences did not reach significance. The "metabolic ratio" of urinary debrisoquine to 4-OHD was less than 3 in all 20 subjects, indicating extensive debrisoquine hydroxylation in every volunteer, including two Chinese individuals known to display slow clearance of desipramine. Contrary to expectation, debrisoquine hydroxylation did not correlate with total or hydroxylation clearance of desipramine in either ethnic group singly or combined. This finding is not consistent with assumptions about the genetic equivalence of the primary metabolic pathways of debrisoquine and desipramine.

Adult↗
PubMed1985

Pharmacokinetics of melatonin in man: first pass hepatic metabolism.

Hepatic clearance concepts were applied to existing data on iv and oral administration of melatonin to man. A high hepatic extraction ratio was calculated, suggesting prominent first pass hepatic metabolism and reduced bioavailability for orally administered melatonin. Using clearance parameters and previous data, endogenous production rates for melatonin were determined for normal individuals and patients with cirrhosis. Normal melatonin production was 28.8 micrograms/day, while the production rate for cirrhotic patients was 12.3 micrograms/day. Thus, not only do cirrhotic patients have decreased melatonin elimination, as noted in the original report, but they also have decreased daily melatonin production.

Administration, Oral↗
PubMed1984

Desipramine pharmacokinetics in Chinese and Caucasian volunteers.

In order to better define the role of pharmacokinetic variation in reported cross-ethnic differences in dosing patterns of some psychoactive drugs, single dose kinetics of the tricyclic antidepressant desipramine (DMI) were studied in 14 Chinese and 16 Caucasian healthy volunteers. DMI and 2-OH-DMI concentrations were assayed with h.p.l.c. in serial plasma and 24 h urine samples over 5 days following an oral 100 mg dose of DMI. Mean total clearance of DMI ( CLDMI ) from plasma was significantly (P less than 0.05) higher in the Caucasians (123 +/- 57 l/h) than in the Chinese (73.5 +/- 38.8 l/h). There was no significant difference in the apparent clearance of DMI by hydroxylation, fraction of dose metabolized to the hydroxy metabolite, DMI t1/2 or plasma protein binding between the two groups. Trimodal distribution of CLDMI was found, with 4/14 (29%) Chinese demonstrating slow CL (less than 33 l/h) and 4/16 (25%) Caucasians rapid CL (greater than 195 l/h). Correcting CL values for the greater mean weight of the Caucasians did not alter the pattern of distribution. CLDMI did not correlate with body weight. Although environmental factors cannot be ruled out, these results are consistent with genetically based differences in hepatic metabolism, probably affecting pathways in addition to hydroxylation, and suggest that 30% of Orientals would be at risk for toxicity from routine doses of tricyclics or similarly metabolized drugs.

Adult↗
PubMed1984

Active metabolites of antidepressants: pharmacodynamics and relevant pharmacokinetics.

This chapter offers a current assessment of the relevance of new findings on the pharmacodynamics and pharmacokinetics of active metabolites of the tricyclic antidepressants. The assessment of TCA actions that may be additive, synergistic, or antagonistic requires precise knowledge of pharmacodynamic potency and control of pharmacokinetic behavior. Simple assumptions about the behavior of ratios of active forms across the populations are inappropriate. Careful pharmacokinetic control is necessary, especially considering that such variables as age, race, illness and other drugs can subtly influence the overall effect by influencing a single active form. The hydroxy metabolites are most susceptible since both their formation and elimination utilize independent variable pathways. Nonetheless, it is now possible to quantitate all known active forms of TCAs. Clinical investigation of the relationship between these forms and specific biochemical effects should provide advances in our understanding of antidepressant mechanisms. On the basis of available data of this type, we conclude that an intensified effort to understand effects secondary to NE uptake inhibition alone would be especially valuable.

Adult↗
PubMed1983

Pharmacokinetic relationships between cinromide and its metabolites in the rhesus monkey I: 3-Bromocinnamamide, an active metabolite.

Fifty percent of a cinromide dose was metabolized to an active metabolite in the rhesus monkey. The steady-state concentration of this metabolite was 3-6 times that of the parent drug, depending on the route of administration. Cinromide is a medium-extraction ratio drug with a short half-life (0.92 +/- 0.23 hr) when compared with the active metabolite, which has a low extraction ratio and a longer half-life (4.43 +/- 0.76 hr). Incomplete oral bioavailability of cinromide is a result of first-pass metabolism rather than incomplete absorption.

Animals↗
PubMed1983

In vivo evaluation of the Michaelis-Menten constant for a medium extraction ratio drug: application to cinromide in the rhesus monkey.

The dose-dependent nonlinearity of the clearance of cinromide, a medium extraction ratio drug, has been established in two monkeys. Special problems encountered in evaluation of nonlinearity of such drugs were resolved by the experimental design: cinromide was infused to steady state via the portal vein. A linearized form of the Michaelis-Menten equation was used to determine Vmax and Km. In addition, cinromide was administered to one of the monkeys via a femoral vein to verify the overestimation of Km by administration at a peripheral venous site.

Animals↗
PubMed1981

Differential kinetics of cinromide and two of its metabolites in epileptic patients.

Cinromide is an experimental anticonvulsant currently in phase II testing. A single oral dose (900 mg) of cinromide was administered to 8 epileptic subjects on phenytoin therapy. Plasma samples drawn during the next 36 h were analyzed for cinromide and its amide and acid metabolites. The absorption rate of cinromide varied widely between subjects producing maximum cinromide concentrations between 0.5 and 2.5 h after the dose. The median elimination half lives of cinromide and the amide and acid metabolites were 0.73, 1.65, and 4.85 h respectively. The oral clearance of cinromide (median = 135 l/h) suggests that it is subject to first pass metabolism. In all subjects the area under the curve (AUC) of acid metabolite (632 to 1777 microM/l) was greater than the AUC of amide metabolite (77 to 185 microM/l) which was greater than the AUC of cinromide (5 to 89 microM/l). Steady-state concentration ratios of metabolite to parent drug predicted from the AUC data were 3.8 for the amide and 35.8 for the acid metabolite. The amide metabolite is known to have anticonvulsant properties and, until the relative contributions of metabolites and parent drug to the efficacy of cinromide are resolved, the monitoring of metabolites as well as parent drug is imperative.

Adult↗
PubMed1981

Metabolite to parent drug concentration ratio as a function of parent drug extraction ratio: cases of nonportal route of administration.

The ratio of metabolite to parent drug concentration (Cm/Cp) of a medium or high extraction ratio (E greater than 0.1) drug administered intravenously has been shown to depend on intrinsic clearance of drug by other metabolic routes (CLr,int) as well as on organ blood flow (Q). In contrast, for a low extraction ratio drug given intravenously or for any drug given by a portal route, this ratio is equal to the ratio of formation clearance (CLf,int) and metabolite clearance (CLm,int). The sensitivity of Cm/Cp to changes in CLr,int and CLf,int has been analyzed quantitatively. It was shown to be dependent on the fraction metabolized to that particular metabolite (fm).

Animals↗