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The influence of concurrent cimetidine administration on the disposition of doxepin was evaluated in 10 healthy volunteers. Each subject ingested 100 mg of doxepin on two different occasions, once while otherwise drug free and once while receiving cimetidine, 300 mg every 6 hours. Doxepin absorptive parameters--time to peak doxepin plasma concentration (2.3, control, vs. 2.4 hours during cimetidine co-administration) and peak concentration achieved (43.3. vs. 55.5 ng/ml)--were not changed during cimetidine administration. Likewise, doxepin elimination half-life was similar in the control state (12.5 hours) and during cimetidine administration (13.2 hours). However, doxepin area under the plasma concentration-time curve (AUC) was increased during concurrent cimetidine administration (533 vs. 695 ng/ml . hour; p less than 0.05), resulting in a trend toward decreased doxepin oral clearance (4404 vs. 3278 ml/min; 0.05 less than p less than 0.1). Relative bioavailability during concurrent cimetidine treatment was 123% of that during the control trial. Desmethyldoxepin AUC was no different between trials (478, control, vs. 433 ng/ml . hour during cimetidine ingestion). Plasma protein binding of doxepin was similar between trials (percent unbound; 10.5, control, vs. 11.2%) and therefore did not influence calculated AUC. These data indicate that doxepin relative bioavailability is increased during concurrent cimetidine administration and suggest that doxepin hepatic extraction is impaired by cimetidine after oral administration. During chronic doxepin therapy, addition of cimetidine to a therapeutic regimen may result in increased doxepin plasma concentration.

In depressed patients treated with doxepin (Sinequan), a 15:85% mixture of cis- and trans-isomers, plasma levels of the cis- and trans-forms of doxepin and desmethyldoxepin were measured using a GLC-method with a capillary column and a nitrogen detector. A gradual increase of the concentration of the products in the plasma is seen in the first days of administration. There is a remarkable variation from patient to patient in the steady-state concentrations of trans-doxepin and of cis- and trans-desmethyldoxepin. cis-Doxepin levels are always very low. It is suggested that for studies of correlation between plasma levels and therapeutic and toxic effects of doxepin, the isomers of the parent compound and its metabolite should be measured separately.

The pharmacokinetics of orally administered doxepin (50 mg) was studied in 8 healthy volunteers. Doxepin (DOX) and desmethyldoxepin (DDOX) concentrations in serum (or plasma) and red blood cells (RBCs) were measured by radioimmunoassay. Peak serum concentrations of DOX were observed at 1-2 hours and they ranged between 59.1-107.4 nmol/1. DOX disappearance was biphasic with a mean distribution half-life of 2.0 hrs and elimination half-life of 17.9 hrs. The mean total apparent volume of distribution was 22.7 l/kg and plasma clearance 0.93 l/hr/kg. The estimated mean first-pass metabolism of DOX was 71% assuming complete absorption. Peak DDOX concentrations were observed at 1-6 hours and they ranged between 35.0-117.8 nmol/l. DDOX elimination was monophasic with a mean apparent half-life of 28.5 hours. Equilibrium dialysis gave a mean protein binding of 75.5% for DOX and 76.0% for DDOX. A highly time dependent and interindividually variable RBC/plasma concentration ratio was observed for both substances. Initially the plasma concentrations were 3-4 times higher than the respective RBC concentrations, but at later time points more DOX and DDOX could be found from the RBCs than from plasma. The major reason for this seemed to be a slower elimination of both drugs from the erythrocytes than from plasma.

Doxepin and N-desmethyldoxepin concentrations in plasma and breast milk from a lactating mother and in plasma from her infant were measured during an 8 week period using high performance liquid chromatography. Plasma concentrations ranged from 35-68 microgram l-1 for doxepin and 65-131 microgram l-1 for N-desmethyldoxepin. Mean pre-feed milk/plasma ratios were 1.08 and 1.02 for doxepin and N-desmethyldoxepin respectively and increased to 1.66 and 1.53 at the post-feed samples. Only N-desmethyldoxepin (15 microgram l-1) was detectable in the infant's plasma sampled after 43 days of maternal therapy.

The pharmacokinetics of two marketed formulations of doxepin HCl administered as a single 100-mg oral dose were compared. Sixteen healthy volunteers between the ages of 21 and 50 years participated in this crossover study. A one-week washout period intervened between doses. Blood samples were drawn before drug administration and at various times up to 48 hours after dosing. The concentrations of doxepin (DOX) and desmethyldoxepin (DDOX), the major active metabolite, were determined. Bioequivalence was determined by statistical comparisons of the area under the curve and maximum concentrations of DOX and DDOX. Statistical comparisons indicated no difference between the two formulations with respect to any of the parameters. The results of this study demonstrate that the two formulations of doxepin HCl are bioequivalent and would be expected to have similar clinical efficacy.

The protein binding of doxepin (DOX) and desmethyldoxepin (DDOX) were studied in serum and plasma samples from healthy volunteers and psychiatric patients. Binding was measured by equilibrium dialysis (16 hrs at 37 degrees) and drug concentrations by radioimmunoassay. In addition, albumin and alpha 1-acid glycoprotein concentrations of the samples were measured by radial immunodiffusion. The mean +/- SEM percentages of unbound DOX were: 20.4 +/- 1.2 and 15.9 +/- 1.2 in healthy subjects (n = 16) and patients (n = 15) respectively, and those of DDOX: 21.4 +/- 0.9 and 19.0 +/- 1.4 for healthy subjects and patients, respectively. There was a significant negative correlation between serum alpha 1-acid glycoprotein concentration and free fraction of DOX in both groups. In healthy subjects a significant negative correlation was also found between albumin concentrations and free fraction of both DOX and DDOX. Binding experiments with isolated protein fractions revealed that all of the total binding in plasma could be explained by binding to albumin and alpha 1-acid glycoprotein. The observed 2--4-fold interindividual variability in the free fractions of these drugs is probably less important than the much larger variability in the total serum concentrations.

In eight healthy young volunteers, 15 g of activated charcoal administered orally 30 min after 50 mg of doxepin, reduced the achieved peak concentration of the drug in serum by 70% and total availability by 49%. Charcoal, 3 hours after the drug, did not significantly reduce absorption. When charcoal was administered 30 min after doxepin, the apparent elimination half-lives of doxepin and its main metabolite, desmethyldoxepin, were prolonged by 350 and 140%, respectively, suggesting gradual disaggregation of the charcoal-drug complex. Repeated doses of charcoal between 3 and 24 hours after doxepin increased significantly the apparent clearance of desmethyldoxepin. Repeated doses of charcoal may be beneficial in the treatment of overdosage with doxepin by preventing disaggregation of the drug from an initial dose of charcoal with subsequent absorption and reabsorption of parent drug and metabolites secreted into the gastrointestinal tract.

The theromdynamic pKa values for doxepin and its metabolite desmethyldoxepin were determined by the solubility method to be 8.96 and 9.75, respectively at 25 degrees. The intrinsic solubilities for doxepin and desmethyldoxepin were linearly dependent upon ionic strength. The intrinsic solubilities at zero ionic strength and 25 degrees were determined to be 1,13 x 10(-4) M for doxepin and 3.95 x 10(-4) M for desmethyldoxepin. The solubility experiment was repeated at different temperatures and a constant ionic strength of 0.167 M. The change in enthalpy (6.71 kcal/mole) and entropy (-4.16 cal/mole degrees K) of solution for doxepin was determined from a van't Hoff plot for this nonideal system. The apparent partition coefficient between hexane and water for the doxepin free base was determined to be 13,615 at an ionic strength of 0.067 M.

Two chromatographic methods, high-performance liquid chromatography (HPLC) and high-performance thin-layer chromatography (HPTLC) were compared for sensitivity and reproducibility in the analysis of the tricyclic antidepressant doxepin and its metabolite, desmethyldoxepin, in plasma. The HPLC procedure yielded a better reproducibility, as reflected by the coefficient of variation, and a higher sensitivity, as reflected by the minimum detectable quantity. The application of these methods for therapeutic and subtherapeutic monitoring of plasma levels of the drug is described.