The pharmacokinetics and bioavailability of clemastine and phenylpropanolamine in single-component and combination formulations.

Studies were conducted in healthy male volunteers (n = 171; age range, 19-49 years; 22-27 subjects per study) to examine the following: pharmacokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of clemastine tablets and combination tablets of clemastine and sustained-release phenyl-propanolamine under fasted and fed conditions after single-dose administration and at steady state. All studies used crossover designs, with randomized drug treatments separated by a 7-day washout period for the single-dose studies, and with administration every 6 or 12 hours for 7 days per treatment for the steady-state studies. After single oral doses of clemastine solution (1,2, and 4 mg), the area under the concentration-time curve (AUC) and maximum concentration (Cmax) were dose proportional. Clemastine showed a first-pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 +/- 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 +/- 315 L) and low Cmax (0.577 +/- 0.252 ng/mL/mg) observed at 4.77 +/- 2.26 hours after administration, and by the biphasic decline in plasma concentration. The terminal elimination half-life (t1/2) of clemastine was 21.3 +/- 11.6 hours. Steady-state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1- and 2-mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t1/2 of phenylpropanolamine, but reduced the rate of absorption of phenylpropanolamine. Combination tablets containing 1 mg or 2 mg of immediate-release clemastine plus 75 mg of sustained-release phenylpropanolamine for twice daily administration were bioequivalent to the separate components and showed no significant interaction with food.

Metabolism of the new immunosuppressor cyclosporin G by human liver cytochromes P450.

Cyclosporin G is a new immunosuppressor structurally similar to cyclosporin A. Although this drug is pharmacologically as active as cyclosporin A, it is less toxic, in particular at the kidney level. The aim of this work was to identify the enzyme system(s) involved in the oxidative metabolism of cyclosporin G in man: (1) in a bank of human liver microsomes (n = 22), cyclosporin G oxidase activity correlated significantly with cyclosporin A oxidase activity (P < 0.0001) and with the level of CYP3A4 (P < 0.002), determined by immunoblot; (2) specific inhibitors of CYP3A4, troleandomycin, and ketoconazole, inhibited cyclosporin G oxidase activity by more than 80%; (3) antiCYP3A4 antibodies specifically inhibited this activity by nearly 90%; (4) cyclosporin A was a competitive inhibitor of cyclosporin G oxidase and vice versa; (5). Among a battery of cDNA-expressed CYPs, only CYP3A4 was able to generate detectable amounts of metabolites of cyclosporin G and cyclosporin A with a turnover number close to that calculated from experiments with liver microsomes; (6) in human hepatocytes in culture, pretreatment of cells with rifampicin and phenobarbital, 2 inducers of CYP3A4, produced a great increase in cyclosporin G oxidase activity, while beta-naphthoflavone, an inducer of CYP1As, did not. We conclude that CYP3A4 is the major enzyme involved in the oxidative metabolism of cyclosporin G in human liver.

Pharmacokinetics and metabolism of cyclosporin G in humans.

The pharmacokinetics and metabolism of cyclosporin G (CsG; Sandoz compound OG 37-325) were studied in 12 healthy male volunteers receiving a single oral dose of 150 or 600 mg of [14C]CsG. Serial blood and plasma samples and complete urine and feces were collected for 120-hr postdose. CsG was rapidly absorbed, and the extent of absorption was dose-independent. Maximum blood concentrations of CsG at 2- to 3-hr postdose averaged 342 and 1170 ng/ml after doses of 150 and 600 mg, respectively, each accounting for approximately 50% of the blood radioactivity level. The plasma:blood concentration ratio for both CsG and total radioactivity averaged approximately 0.8. Overall disposition of absorbed CsG was independent of the dose. The drug was extensively metabolized with excretion predominantly via the fecal route. Total recovery in urine was only approximately 3% of the dose. In blood, the terminal half-life of CsG and total radioactivity averaged 9-11 hr following both the 150 and 600 mg doses. In plasma, the half-life of CsG was 2-4 hr and that of total radioactivity was 27-29 hr. The major metabolic pathways resulted from oxidative modifications at amino acids 1, 4, and 9, with concomitant cyclization of amino acid 1 in two metabolites. These pathways resulted in formation of seven major metabolites (designated GM19, GM1c9, GM4N9, GM1, GM9, GM1c, and GM4N) observed in human excreta and/or blood. Major metabolites of CsG in blood involved monohydroxylation (GM1 and GM9) or demethylation (GM4N). In blood, monohydroxylated CsG metabolites (GM1 and GM9) achieved roughly equal levels, with a trend toward higher GM9 concentrations at peak radioactivity.

Increased circulating levels of bromocriptine after vaginal compared with oral administration.

OBJECTIVE: To compare the circulating levels of bromocriptine after oral and vaginal administration of the drug. DESIGN: Experimental PARTICIPANTS: Seven ovulatory female volunteers and one hyperprolactinemic patient. INTERVENTIONS: Ovulatory volunteers were randomized to receive either oral or vaginal bromocriptine (2.5 mg). In a second session, the subjects were crossed-over to bromocriptine by the alternate route. An additional hyperprolactinemic patient received vaginal bromocriptine only. MAIN OUTCOME MEASURE: Serum bromocriptine and prolactin (PRL) levels were measured hourly for 12 hours in the normal volunteers and for 10 hours in the hyperprolactinemic patient. RESULTS: Circulating bromocriptine levels were significantly higher after vaginal bromocriptine after the 7th hour (P less than 0.05). The reduction in serum PRL was significantly greater after oral administration between 2 and 6 hours. CONCLUSIONS: Vaginally administered bromocriptine may result in a reduction in the overall dose required, thereby improving compliance without compromising therapeutic efficacy.

Bioavailability of isradipine in young and old rats: effect of mode of administration.

The bioavailability of isradipine has been examined in 7- and 52-week-old rats after oral (12.5 mg kg-1) or intravenous (2.5 mg kg-1) doses as a solution and administration of various doses (1.8-85.5 mg kg-1) in the diet. Serial plasma samples were obtained from each rat and the drug concentration was determined by radioimmunoassay. Absorption from the dose given by gavage was rapid but when administered in a drug diet mixture, isradipine appeared in the plasma slowly and in a manner reflecting the feeding pattern. Its absolute bioavailability from the drug-diet mixture averaged 3% over the dose range tested. By gavage its bioavailability was enhanced to 5% of dose with peak plasma values approximately 7 times higher than from a comparable dose in the diet. The low oral bioavailability of isradipine in the rat was most likely due to extensive first-pass metabolism. The decline in plasma concentrations was biexponential, with a mean terminal half-life of 3.6-3.7 h after oral or intravenous dosing. The pharmacokinetic characteristics of isradipine examined were independent of the age of the rat, except that its volume of distribution decreased with age. The older rats also showed a greater inter-animal variability in isradipine bioavailability from the drug-diet mixture.

Successful treatment of a prolactin-producing pituitary macroadenoma with intravaginal bromocriptine mesylate: a novel approach to intolerance of oral therapy.

A 37-year-old woman with a symptomatic 18-mm prolactin-secreting pituitary adenoma could not be managed with oral bromocriptine mesylate because of unacceptable gastrointestinal side effects. However, when given the medication intravaginally, the patient was successfully treated as assessed by evident tumor shrinkage and diminished secretory activity. Serum bromocriptine levels were approximately six to eight times higher than those reported after oral administration. The vaginal route may help reduce some of the adverse effects of bromocriptine mesylate experienced during oral administration and may possibly allow lowering of the overall effective dose by avoiding first liver passage.

The effects of renal function on the disposition of isradipine.

The effect of renal function on isradipine kinetics was examined in four groups of subjects (N = 55) who had normal or impaired renal function. Each subject received isradipine orally as a 10-mg capsule. Serial blood samples were obtained from 0 to 48 hours postdose and the isradipine plasma concentrations determined by radioimmunoassay. Kinetic parameters, Cmax, lambda 3, t 1/2, AUC, CL'o (oral clearance), and CLo (oral clearance standardized to body weight) were determined. Marked intersubject variability of the pharmacokinetic parameters was observed. No statistically significant differences (P greater than .05) were found for AUC, Cl'o, and Clo parameters when renal impairment groups were compared with controls. AUC values were lower (P less than .05), however, for the group with severe renal function impairment than for groups with mild or moderate renal function impairment. No significant correlations (r = -.23, P greater than .05; and r = .13, P greater than .05, respectively) were found between creatinine clearance (CLCR) and CLo and between age and CLo. Considering the interpatient variability in isradipine disposition and the lack of significant differences in CLo between groups, no clear-cut dosing regimen alterations, based on single-dose data, are warranted in renal impairment.

Pharmacokinetics and bioavailability of ergoloid mesylates.

The pharmacokinetics and bioavailability of ergoloid mesylates following single administrations of various dose levels (3-9 mg), dosage forms (oral swallow and sublingual tablets, solution) and under different dosing conditions (fasted, with meal) were studied in young healthy volunteers. Male and female subjects showed a similar rate and extent of bioavailable ergoloid after drug treatment. The absorption of ergoloid using either the tablet dosage forms or the drug administered as a solution was rapid, with peak levels of about 60-80 pg ml-1 mg-1 dose achieved after 0.6 to 1.3 h. The elimination half-life for ergoloid in plasma was 2-5 h. Administration of drug with food had no effect on the extent of absorption (AUC) but lowered the absorption rate. This resulted in a reduction of (by 25 per cent) and delay in (by 1 h) achieving peak levels (Cmax). Increasing the ergoloid dose caused a proportional increase in the AUC, but a smaller than proportional increase for Cmax. The tablet formulations provided similar AUCs as the solution; the objective of the sublingual tablet formulation to provide improved bioavailability over the swallow tablet via circumvention of first-pass metabolism was therefore not realized. Transient decreases in blood pressure after ergoloid treatment paralleled the plasma level profiles. Higher ergoloid levels were paired with the larger pressure decreases.

The pharmacokinetics of oral isradipine in normal volunteers.

The pharmacokinetics and relative bioavailability of oral isradipine, a dihydropyridine calcium channel blocking agent, were determined in 42 normal male volunteers participating in two separate studies. Eighteen of the subjects received 2.5-, 5-, and 10-mg oral doses of isradipine solution (Study 1). The remaining 24 subjects received four 2.5-mg capsules, one 10-mg capsule, and 10 mg of isradipine as an oral solution (Study 2). Venous blood samples were obtained prior to and at frequent intervals after administration of each dose form. Plasma isradipine concentrations were measured by radioimmunoassay. No significant dose effect occurred with respect to any pharmacokinetic parameter except AUC and Cmax in Study 1. In Study 2, Cmax, tmax, and MRT were significantly different after the solution compared with the capsular formulations. The respective pharmacokinetic parameters (mean +/- SD) for the 10-mg solution and 10-mg capsule in Study 2 were time to maximum concentration, 0.40 +/- .28 and 1.57 +/- 0.44 hours; oral clearance, 284.9 +/- 105.3 and 317.0 +/- 138.4 L/hr; elimination half-life, 5.36 +/- 1.8 and 6.63 +/- 2.4 hrs, respectively. Headache, dizziness, and tachycardia were the most frequent adverse effects in both studies.

Determination of cyclosporine concentrations with monoclonal antibodies.

We measured cyclosporine in whole blood from normal volunteers administered single oral doses of the drug and from two renal-transplant patients on immunosuppressive maintenance therapy, by liquid chromatography (I) and by radioimmunoassay with use of nonspecific polyclonal (II), specific monoclonal (III), and nonspecific monoclonal (IV) antibodies. Concentrations determined by III were equivalent to I, irrespective of cyclosporine dose, concentration, time after dose, or time after transplant. Concentrations determined by II and IV were consistently higher than those by I, owing to cross reactivity with metabolites. Ratios of values by II and IV to those by I increased from less than 1.5 to about 3-4 between 0.5 and 12 h after a single cyclosporine dose, owing to differences in rates of appearance and disappearance of cyclosporine and cross-reacting metabolites, though for the constant 12-h dose intervals in the two renal-transplant patients at steady state these ratios (most within the range 3-4) were relatively stable. Ratios of concentrations measured by IV to those by II (mean of 1.2 for single-dose data, most within the range of 1.2 to 1.5 at steady state) were unaffected by time after dose or time after transplant, suggesting that, despite certain cross-reactivity differences between the two nonspecific antibodies, results are proportional throughout therapy. We therefore propose that III and IV offer alternatives, respectively, to the currently used I and II for cyclosporine monitoring.

Pharmacokinetics and pharmacodynamics of bromocriptine in the rat.

The absorption, distribution, and excretion of bromocriptine were studied following oral and parenteral administration of non-radioactive and 14C-labelled drug in the rat. Total radioactivity was measured in blood, tissues, and excreta by liquid scintillation counting while the parent drug was determined in plasma and selected tissues by radioimmunoassay. The pharmacokinetic observations were compared with the time course of drug-induced hypothermia in cold-room acclimatized rats. The results indicated that oral doses of bromocriptine were rapidly, though incompletely (32-40 per cent), absorbed, but underwent extensive first-pass metabolism, resulting in an absolute bioavailability of only 6 per cent. The bioavailability increased to approximately 22 per cent in rats pretreated with the hepatic microsome inhibitor proadifen, thus suggesting the liver as the principal site of biotransformation. Absorbed bromocriptine showed preferential distribution into the tissues, although no apparent accumulation of drug-related material occurred in the body. The drug was eliminated almost exclusively by metabolism and biliary excretion into the faeces. Comparison of the pharmacodynamic and the pharmacokinetic profiles indicated a dose relationship between hypothermia and plasma bromocriptine concentrations but not total radioactivity levels. The hypothermic response was also intensified by proadifen pretreatment, thus confirming the parent drug as the pharmacologically active entity. It is believed that the previously reported delay in the onset of bromocriptine activity is not pharmacokinetic in nature, but is related to the properties of the receptors at the target site or to the pharmacologic events that result in the observed effects.

Pharmacokinetics of dihydroergotamine following subcutaneous administration in humans.

The pharmacokinetics of dihydroergotamine was studied following a 1.5-mg subcutaneous dose of the mesylate salt in six healthy volunteers. Plasma and urine dihydroergotamine, determined using a specific radioimmunoassay, were simultaneously fitted to equations consistent with a two-compartment open model. The drug was rapidly absorbed from the injection site; peak plasma concentrations of 3-8 ng/ml were observed within 15-45 min of dosing. Half-lives for the rapid and slow phases of decline in plasma dihydroergotamine were 0.95 and 7.26 h, respectively. The overall volume of distribution was 14.6 l/kg. The plasma clearance and renal clearance values were 1814 and 91 ml/min, respectively, indicating that 5% of the dose was excreted unchanged in the urine. Comparison of the results of the present study to published data confirmed that dihydroergotamine is eliminated from the body predominantly by metabolism.

Bioavailability of ergoloid mesylates liquid capsule.

Bioavailability of two formulations of ergoloid mesylates was compared in 18 healthy men. In a randomized, crossover design, each subject received a single oral dose of six liquid capsules and six oral tablets, each capsule or tablet containing 1 mg of the active ingredient. A one-week washout period intervened between the two doses. Blood samples were drawn at intervals up to ten hours after drug ingestion and were assayed for plasma concentrations of ergoloid mesylates by a specific radioimmunoassay. The liquid capsule produced mean peak concentrations and areas under the curve (AUC) that were about 12% higher than those produced by the oral tablet; these differences were statistically significant (P less than 0.05). No statistically significant differences were observed for the other pharmacokinetic parameters, namely, time to peak concentration, apparent rate constants for absorption and elimination, and lag time. As the differences in peak concentration and AUC were less than 20%, even though they were statistically significant, the two formulations were considered bioequivalent according to FDA guidelines for bioequivalence. The therapeutic benefit that might derive from greater bioavailability of the liquid capsule has not been established.

Acquired immune deficiency syndrome. No evidence of the presence of cyclosporine.

It has been postulated that the acquired immune deficiency syndrome (AIDS) may be a result of the systemic presence of an immunosuppressive cyclosporine-like molecule released in chronic fungal infections. This possibility was examined by analysis of blood, plasma, or serum samples obtained from AIDS patients, from subjects with prodromal AIDS, and from healthy subjects belonging to several of the recognized "AIDS risk groups" for cyclosporine-like substances. The sensitivity of the analytic methods and the stability of cyclosporine during the storage of blood were verified by analysis of blood specimens obtained from a normal volunteer after oral ingestion of various doses of cyclosporine. Radioimmunoassay, high-pressure liquid chromatography, and analysis by combination of these two methods failed to detect cyclosporine or cyclosporine-like substances in subjects with established or prodromal AIDS and in AIDS-free persons belonging to the risk groups. These results indicate that the breakdown of cellular immunity in AIDS is not due to circulating cyclosporine.

Mesulergine, a new dopamine agonist: effects on anterior pituitary function and kinetics.

We investigated the effects of single doses of mesulergine on basal and thyrotropin-releasing hormone (TRH)-stimulated serum levels of several anterior pituitary hormones in healthy men and defined its kinetics. We also compared the effects on serum prolactin (PRL) levels of three doses (0.1, 0.35, and 0.5 mg) of mesulergine to those in response to 2.5 mg bromocriptine. Secretory rates of PRL before the first dose of TRH were not affected by any dose of mesulergine or bromocriptine. TRH-stimulated PRL secretion was not altered by 0.1 mg mesulergine but was blunted by both the 0.35- and 0.5-mg doses at 10 A.M. and 1 P.M. Bromocriptine inhibited TRH-stimulated PRL secretion at 10 A.M. and 8 P.M. When analyzed as the 8 A.M. to 8 P.M. and the 8 P.M. to 9 A.M. (day 2) intervals, PRL secretion was not changed by 0.1 or 0.35 mg mesulergine but was suppressed during both periods by the 0.5-mg dose. A dose-response relationship was evident, however, between mesulergine and PRL secretion during both the 8 A.M. to 8 P.M. (R2 = 0.27) and the 8 P.M. to 9 A.M. (day 2; R2 = 0.18) intervals. Bromocriptine lowered PRL secretion during both intervals. Secretory rates of growth hormone during these intervals were not affected by 0.1 mg or 0.35 mg mesulergine but were increased during both intervals by the 0.5-mg dose. Neither the secretory rates of thyrotropin in response to TRH nor those of cortisol, luteinizing hormone, or follicle-stimulating hormone were changed by 0.1 or 0.35 mg mesulergine.(ABSTRACT TRUNCATED AT 250 WORDS)

Low dose bromocriptine: a study of acute effects in chronic mediated schizophrenics.

An acute low oral dose (2 mg) of bromocriptine was administered in a randomized double blind fashion to 11 chronic symptomatic mediated schizophrenic patients. There was an overall improvement for the group on the Brief Psychiatric Rating Scale (BPRS) following bromocriptine. Plasma homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and vanilloyl-mandelic acid concentrations were unchanged after bromocriptine. Bromocriptine concentrations in the plasma showed a large inter-individual variation. There was a significant inverse correlation between plasma bromocriptine concentration and total BPRS score at 60 minutes post-bromocriptine administration. These results suggest a need for further replication in a larger study population and a need for controlled studies with chronic administration of low dose bromocriptine in chronic medicated schizophrenic patients.

The pharmacokinetics and bioavailability of subcutaneously administered dihydroergotamine, heparin and the dihydroergotamine-heparin combination.

Subcutaneously administered dihydroergotamine (DHE) becomes rapidly and completely available to the human systemic circulation, with peak plasma levels of 1.4-3.5 ng/mL/mg achieved in less than 1 h. The elimination of DHE from plasma is biphasic, t 1/2 alpha = 1h, t 1/2 beta = 4-5 h. DHE exhibits linear dose proportionality. Coadministration of heparin results in a statistically significant increase of 25% in the area under the plasma level/time curve for DHE (bioavailability). Coinjection of DHE and heparin in the same subcutaneous site furthermore causes a decrease in the rate of DHE absorption by 63%, resulting in delayed time to peak (by 110%) and reduced peak levels (by 15%) of DHE. In contrast, there is no effect by coadministered DHE on heparin pharmacokinetic parameters. Heparin peak plasma levels (0.3 I.U./mL by activated factor X, 0.1 I.U./mL by protamine titration with a 15,000 I.U. s.c. bolus) are achieved in 3.6 h. Pharmacokinetic analysis suggests that the subcutaneous route of administration provides only 19% of the bioavailable heparin that would be obtained following administration of an equipotent intravenous dose. DHE-heparin formulated for injection in combination demonstrates systemic availability identical to that of the two components injected separately, but with a reduced rate of absorption for the DHE component and a corresponding attenuation of fluctuations in steady state DHE levels.