James M Hilbert

Excretion of Loratadine in Human Breast Milk

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40‐mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration‐time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration‐time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk‐plasma AUC ratio was 1.2 and 4.2 μg of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8‐hour collection interval. Through 48 hours, the mean milk‐plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 μg of descarboethoxyloratadine (7.5 μg loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 μg loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4‐kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis. An estimated “worst‐case” dose (i.e., the maximum dose that could be expected under any circumstances) of loratadine and descarboethoxyloratadine to an infant was calculated to be only 1.1% of the adult loratadine dose on a mg/kg basis. The adult dose has been reported to be safe and well tolerated, so it is unlikely that this dose presents a hazard to infants.

Loratadine: multiple-dose pharmacokinetics

The steady‐state pharmacokinetics of loratadine (L), a new long‐acting antihistamine devoid of CNS activity, was investigated in 12 healthy male volunteers. Each volunteer received 40‐mg L capsules q24h for ten days. Blood samples were collected at various times on day 1, 5, 7, and 10 and assayed for L by radioimmunoassay (RIA) and for descarboethoxyloratadine (DCL), a known active metabolite, by high‐performance liquid chromatography (HPLC). The plasma L and DCL concentration‐time data in the disposition phases were fitted to a biexponential equation for pharmacokinetic analysis. Steady‐state plasma L Cmax concentrations were reached at 1.5 hour (Tmax) after each dose. DCL steady‐state Cmax values ranged 26 to 29 ng/mL at a Tmax ranging from 1.8 to 3 hours. The AUC at steady state, AUCτ, was 80 to 96 and 349 to 421 h × ng/mL for L and DCL, respectively. The accumulation indexes (Ra) based on AUCτ ratios, did not change for either compound after day 5. Ra values for L and DCL after the fifth dose were 1.4 and 1.9, respectively, indicating that there is little accumulation of either L or DCL after a multiple (once‐a‐day) dosage regimen. The t1/2β at steady state were 14.4 and 18.7 hours for L and DCL, respectively, which were similar to those reported following a single‐dose L administration. Observed plasma drug concentrations were in good agreement with predicted values derived for pharmacokinetic parameters.

Excretion of Quazepam Into Human Breast Milk

Abstract: Previous metabolic studies have established that two major metabolites, 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam, are present in plasma after dosing with quazepam, a new benzodiazepine hypnotic. The excretion of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam into human breast milk was studied in four lactating nonpregnant volunteers. Each volunteer received one 15‐mg quazepam tablet following an overnight fast. Nursing of offspring was discontinued after drug administration. Milk and blood samples were collected prior to and at specified times (up to 48 hours) after dosing. Plasma and milk levels of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam were determined by specific GLC methods. The concentrations of the three compounds found in milk appeared to depend on their relative lipophilicities, which were determined by log P values. The mean milk/plasma AUC ratios of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam were 4.19, 2.02, and 0.091, respectively. Levels of quazepam and 2‐oxoquazepam declined at about the same rate in plasma and in milk. The total amount of the administered quazepam dose found in the milk as quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam through 48 hours was only 0.11 per cent.

The Pharmacokinetics of Loratadine in Normal Geriatric Volunteers

The pharmacokinetics of loratadine, a non-sedating anti-histamine, were studied in 12 normal geriatric volunteers. In an open label fashion, each volunteer received one 40 mg loratadine capsule. Blood was collected prior to and at specified times (up to 120 h) after dosing. Plasma loratadine concentrations were determined by a specific radioimmunoassay and those of an active metabolite, descarboethoxyloratadine, by high performance liquid chromatography. Concentrations of loratadine in the disposition phase were fitted to a biexponential equation and those of descarboethoxyloratadine to either a monoexponential or biexponential equation for pharmacokinetic analysis. Loratadine was rapidly absorbed, reaching a maximum plasma concentration of 50.5 ng/ml at 1.5 h after dosing. The disposition half-lives of loratadine in the distribution and elimination phases were 1.5 and 18.2 h, respectively. The area under the plasma concentration–time curve, was 146.7 h·ng/ml. Descarboethoxyloratadine had a maximum plasma concentration of 28.0 ng/ml at 2.9 h post-dose and an area under the concentration–time curve of 394.9 h·ng/ml. Its disposition half-lives in the distribution and elimination phases were 2.8 and 17.4 h, respectively. Comparison of these data with those from a previous study of loratadine in young adults showed no clear differences in the disposition half-lives between the two groups. The clearance of loratadine tends to be lower in the elderly, but inter-individual variation within each age group appears greater than any age effect.

Pharmacokinetics of loratadine in patients with renal insufficiency

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearances less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2β were observed between the three groups (8.7 ± 5.9, 7.6 ± 6.9, 8.6 ± 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC0∞ however was significantly greater in group II subjects: (212.4 ± 37.8, 469.5 ± 95.4, 325.2 ± 114.6 ng · hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half‐life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.

Effect of sleep on quazepam kinetics

The effect of sleep on quazepam kinetics was studied in 12 normal adult men. In a randomized two‐way crossover design, each subject received one 15‐mg quazepam tablet either at night just before sleep or in the morning after a nights sleep. Blood samples were drawn before and at specified times (to 120 hr) after dosing. To assure that blood collection did not interfere with sleep, blood was drawn by an indwelling catheter from a large arm vein. Plasma concentrations of quazepam and its two major plasma metabolites (which are also active) 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam (N‐desalkylflurazepam) were determined by specific GLC methods. Kinetic analysis was by a two‐compartment open model with first‐order absorption/formation kinetics. Quazepam was rapidly absorbed with both administration times; absorption t½ was 0.7 to 0.9 hr. Absorption lag time was slightly longer after the nighttime dose (1.0 and 0.6 hr). Maximum concentration and AUC of quazepam and 2‐oxoquazepam and AUC of N‐desalkyl‐2‐oxoquazepam were somewhat higher after nighttime dosing, most likely a result of decreased apparent volume of distribution of the central compartment after the nighttime dose (5.0 l/kg for nighttime dosing and 8.6 l/kg for morning dosing). The elimination t½s of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam after the morning dose were 25, 28, and 79 hr, which did not differ from those values after the nighttime dose. In general, time of dosing had no appreciable effect on quazepam kinetics or those of its major active plasma metabolites. The small differences between the two dose times are not expected to have clinical significance.

Multiple‐dose quazepam kinetics

Quazepam, a benzodiazepine hypnotic, was studied in normal subjects to evaluate steady‐state kinetics of quazepam and of its major active plasma metabolites, 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam, after 15 mg once daily by mouth for 14 days. The kinetics of quazepam and 2‐oxoquazepam can be best described by a two‐compartment open model with first‐order absorption/formation kinetics. Quazepam was rapidly absorbed and its two major plasma metabolites appeared very quickly in systemic circulation. The elimination t½ of quazepam, 2‐oxoquazepam, and N‐desalkyl‐2‐oxoquazepam were 41, 43, and 75 hr. Steady‐state levels were predictable from the kinetic data and were reached by the seventh dose for quazepam and 2‐oxoquazepam and by the thirteenth dose for N‐desalkyl‐2‐oxoquazepam. These kinetic profiles may explain the clinical hypnotic effect of quazepam—rapid induction of sleep and long duration of clinical action without appreciable rebound insomnia.

Quazepam kinetics in the elderly

The kinetics of quazepam, a benzodiazepine hypnotic, was studied in 10 geriatric subjects. Each received one 15‐mg tablet of quazepam. Blood samples were collected before and at specified times (up to 672 hr) after dosing. Plasma concentrations of quazepam and its two major active plasma metabolites, 2‐oxoquazepam and N‐desalkyl‐2‐oxoquazepam (N‐desalkylflurazepam), were determined by specific GLC methods. Kinetics were best described by a two‐compartment open model with first‐order absorption/formation kinetics and standard equations. Quazepam was rapidly absorbed, with a t½ of 0.8 hr. The mean maximum plasma level (Cmax) was 29.3 ng/ml. The disposition t½s in the distribution (t½α) and elimination (t½β) phases were 3.5 and 53.3 hr. 2‐Oxoquazepam was rapidly formed with quazepam, with an apparent formation t½ of 0.8 hr. Mean Cmax was 14.5 ng/ml. The t½α and t½β of 2‐oxoquazepam were 4.2 and 43.1 hr, of the order of those of quazepam. The t½β of N‐desalkyl‐2‐oxoquazepam, formed from 2‐oxoquazepam, was 189.7 hr, much longer than that of its precursor. Comparison of these data with reported kinetic data in young subjects shows that t½βs of quazepam and 2‐oxoquazepam increased only slightly or not at all with age, but that the t½β of N‐desalkyl‐2‐oxoquazepam in the elderly was more than twice that in young subjects.

Relationships of brain and plasma levels of quazepam, flurazepam, and their metabolites with pharmacological activity in mice

The relationships between the pharmacological activities of quazepam and flurazepam and the concentrations of each drug and its major active metabolites in brain and plasma following single oral doses of either drug to mice were investigated. At various time points after either quazepam or flurazepam administration, pharmacological activity was measured by the inhibition of electroconvulsive shock (ECS)-induced seizures. After quazepam, the plasma and brain samples obtained at the same time points were assayed for concentrations of quazepam, 2-oxoquazepam and N-desalkyl-2-oxoquazepam by specific GLC methods. After flurazepam, the plasma and brain samples were assayed for flurazepam, hydroxyethyl-flurazepam, and N-desalkyl-2-oxoquazepam, also by specific GLC methods. The results showed that both quazepam and flurazepam were rapidly metabolized and that parent drugs and metabolites were rapidly distributed to the brain. The brain levels of all the benzodiazepines analyzed in this study paralleled plasma levels. After quazepam, pharmacological activity most closely paralleled the combined brain concentrations of quazepam and 2-oxoquazepam rather than N-desalkyl-2-oxoquazepam levels. In contrast, following the flurazepam dose, activity most closely paralleled N-desalkyl-flurazepam concentrations. From these data, it can be concluded quazepam is distinctly different from flurazepam, and that, in the presence of quazepam and 2-oxoquazepam, N-desalkyl-2-oxoquazepam does not contribute extensively to the observed pharmacological activity.

Multiple‐dose halazepam kinetics

Halazepam is a benzodiazepine used in the management of anxiety disorders or short‐term relief of anxiety. Our study was undertaken to evaluate its steady‐state kinetics and those of its major active plasma metabolite N‐desalkylhalazepam. Eleven healthy men aged 19 to 35 yr were given oral, 40‐mg halazepam tablets every 8 hr for 14 days. Plasma samples were analyzed by gas chromatography to determine levels of halazepam and N‐desalkylhalazepam. Halazepam kinetics can best be described by a two‐compartment open model with first‐order absorption kinetics. The elimination phase t½s of halazepam and N‐desalkylhalazepam were 34.7 and 57.9 hr. Steady‐state levels were predictable from kinetic data and were reached by the third day for halazepam and by the eleventh day for N‐desalkylhalazepam.