Influence of the antibiotics erythromycin and azithromycin on the pharmacokinetics and pharmacodynamics of midazolam.

The pharmacokinetic and pharmacodynamic interaction between azithromycin (CAS 83905-01-5), an azalide antibiotic, and midazolam (CAS 59467-70-8), a short-acting hypnotic agent, was investigated in an open, three-way cross-over study, including erythromycin (CAS 114-07-8) as a positive control. Twelve healthy male and female subjects had standard doses of azithromycin (500 mg o.d. over 3 days), or erythromycin (500 mg t.i.d. over 5 days), or no pretreatment. On the day of the last dose, they ingested 15 mg midazolam. Blood samples were collected and psychometric tests performed. Erythromycin pretreatment (E) significantly changed the pharmacokinetics of midazolam compared to control (C), whereas azithromycin (A) had no such effect. The parameters are summarized as follows: area under the concentration-time curve, AUC (C) 173.8 h.ng.ml-1 vs. (E) 662.7 h.ng.ml-1*+ and (A) 220.0 h.ng.ml-1; concentration maxima (C) 67.2 ng.ml-1 vs. (E) 182.3 ng.ml-1*+ and (A) 86.7 ng.ml-1; elimination half-life (C) 2.21 h vs. (E) 4.85 h* and (A) 2.41 h (* p < 0.05 vs. (C), +p < 0.05 vs. (A)). Pharmacodynamic tests (digit symbol substitution test; critical flicker fusion test; subjective analog scale for rating of alertness; duration of sleep) consistently showed significant differences after erythromycin pretreatment compared to control, but not after azithromycin. Erythromycin, but not azithromycin, causes clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.

Enantioselective gas chromatographic assay with electron-capture detection for amlodipine in biological samples.

A sensitive enantioselective gas chromatographic assay has been developed for amlodipine, 2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5- methoxycarbonyl-6-methyl-1,4-dihydropyridine, a calcium channel blocking therapeutic agent. The assay involves conversion of the (+)-(R)- and (-)-(S)-enantiomers of amlodipine into their acyl derivatives with the chiral reagent (+)-(S)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride (Mosher's reagent). Peak separation after chromatography of the diastereomers was larger than 85%, and the lower limit of detection in blood plasma was 0.02 ng/ml for each enantiomer. The method has been used for the measurement of amlodipine enantiomers in human, rat and dog plasma, and in various organs of the rat.

Pharmacological comparison of the stereoisomers of glyceryl-1-nitrate.

The enantiomers of glyceryl-1-nitrate, a metabolite of glyceryl trinitrate, were pharmacologically characterized in vitro and in animals. In the Langendorff heart (l) G-1-N was double as potent as (d) G-1-N with respect to the enhancement of coronary flow. The two enantiomers showed almost the same dose-response curves in rabbit aortic strips contracted with phenylephrine. In the same model there were no enantiospecific differences in the development of cross-tolerance to glyceryl-trinitrate. In anaesthetized rabbits, intravenous (l) G-1-N reduced the blood pressure slightly more than (d) G-1-N, while in the conscious dog the blood pressure lowering effect of (d) G-1-N was greater and had a much longer duration (4-6 versus 2 h) than that of (l)G-1-N. The differences in dogs are probably explained by enantiospecific pharmacokinetics: (d) G-1-N had higher plasma levels and showed a longer half-life of elimination than (l) G-1-N (more than 5 h versus 2.7 h). Both enantiomers enhanced the rate of survival after acute coronary ligature in rats with a tendency to higher long-term survival rates after the (d) form.

Enantioselective disposition of oral amlodipine in healthy volunteers.

Plasma concentrations of (R)- and (S)-amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)-enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)-enantiomer, with mean values of 47% R to 53% S for the Cmax and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)-form was subject to much less intersubject variation (25% CV) than that of the inactive (R)-form (52% CV). (R)-Amlodipine was more rapidly eliminated from plasma than (S)-amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). The terminal half-lives of total amlodipine (mean 44.2 h) were strongly correlated with--and thus highly predictive for--the half-lives of the (S)-enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers.

Comparison of the pharmacokinetics of three-day and five-day regimens of azithromycin in plasma and urine.

In an open crossover study, the pharmacokinetics of three-day and five-day regimens of azithromycin were compared. Fourteen healthy volunteers received oral doses of azithromycin once-daily, over three days (500 mg/day) and over five days (500 mg on day 1, followed by 250 mg/day on days 2-5). Plasma and urine concentrations were determined by HPLC. Azithromycin was found to be absorbed rapidly on the first and the last days of both regimens, with mean Tmax ranging between 2.5-3 h. On day 1, peak plasma concentrations were 0.37 mg/L and 0.31 mg/L, respectively, with three- and five-day regimens, and increased to 0.42 mg/L on the last day of the three-day regimen, but decreased to 0.18 mg/L at the end of the five-day regimen. Similarly, the AUC0-24 increased from 1.30 to 1.88 h.mg/L during the three-day regimen, and decreased from 1.24 to 0.80 h.mg/L on the five-day regimen. After absorption, azithromycin was distributed rapidly; the respective half-lives were 2.4 h and 2.2 h with the three-day and five-day regimens. Thereafter, a polyphasic decline of plasma concentrations was observed; the average half-lives between 8-48 h after administration were 27.9 h (three-day regimen) and 35.8 h (five-day regimen). In urine, 5.5% (three-day regimen) and 4.6% (five-day regimen) of the total dose was found as unchanged azithromycin over a 12-day period. The observed pharmacokinetics of azithromycin with both regimens conformed with the known pharmacokinetic behaviour of the drug. The treatment-related differences seen in the plasma concentrations were as expected from the different dosage schedules.

Bioavailability and metabolism of isosorbide dinitrate from a transdermal spray.

The plasma pharmacokinetics of isosorbide dinitrate (ISDN), isosorbide-2-nitrate (IS-2-N) and isosorbide-5-nitrate (IS-5-N) were investigated in 12 healthy volunteers after a single cutaneous administration of 60 mg ISDN (CAS 87-33-2) in the form of a solution sprayed onto the skin (TD Spray Iso Mack), in comparison with an intravenous infusion of 5 mg ISDN. After the intravenous dose, the apparent steady state volume of ISDN distribution came to 179.9 l, total body clearance was 3.14 l min-1, and terminal half-life was 79 min, on average. The transdermal absorption resulted in an average peak plasma concentration of 6.9 ng ISDN ml-1 at 5 h after the administration. ISDN concentrations between 1 and 5 ng ml-1 were maintained over at least 15 h. On average, 16.5% of the topically applied ISDN reached the systemic circulation. Total variations in Cmax (CV = 47.9%) and AUC (CV = 36.0%) of transdermal ISDN were similar to those usually observed after oral ISDN.

Comparison of isobutyl nitrate and isobutyl nitrite: tolerance and cross-tolerance to glyceryl trinitrate.

This study includes the first systematic comparison of an organic nitrate with the corresponding organic nitrite-isobutyl nitrate and isobutyl nitrite. The spasmolytic activity of the nitrite on isolated rabbit aortic strips was stronger, more rapid in onset, but less stable than the activity of the nitrate. In vitro tolerance to glyceryl trinitrate and isobutyl nitrite greatly weakened the activity of isobutyl nitrate, respectively, but had much less effect on isobutyl nitrite. Possible reasons for these differences are discussed.

Antagonism of glycerol trinitrate activity by an inhibitor of glutathione S-transferase.

The in vitro spasmolytic activity of glycerol trinitrate was measured on the KCl-contraction of aorta strips from the rabbit. In the presence of sulphobromophthalein, a known inhibitor of glutathione S-transferase, the dose-activity curve for the nitrate was displaced to the right. Much smaller displacements were obtained with the control spasmolytic substances--papaverine and S-nitroso-N-acetylpenicillamine. It was confirmed that sulphobromophthalein inhibits glutathione S-transferase activity in aorta homogenates. Aorta extracts did not detectably catalyze the reaction between glutathione and sulphobromophthalein and the glutathione level was not decreased by treating the intact aorta with sulphobromophthalein. It is concluded that sulphobromophthalein acts as a specific antagonist of the spasmolytic activity of glycerol trinitrate, probably as a result of its inhibition of glutathione S-transferase. It thus seems probable that glutathione and glutathione S-transferase are involved in the pharmacological activation of the organic nitrates.

Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate.

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)

The pattern of glyceryl nitrates after oral administration of glyceryl trinitrate.

An oral dose of 20 mg sustained release glyceryl trinitrate (GTN, Nitro Mack Retard) was administered to 6 healthy human subjects. In the plasma of all subjects the metabolically generated glyceryl nitrates glyceryl 1,2-dinitrate (G-1,2-DN), glyceryl 1,3-dinitrate (G-1,3-DN), glyceryl 2-nitrate (G-2-N) and glyceryl (G-1-N) could be identified, but no intact GTN was found. The nitrate metabolites showed sustained plasma profiles which can be explained by a slow release of GTN with subsequent complete first-pass denitration. The plasma concentrations of the mononitrates were generally higher than those of the dinitrates. G-1,2-DN and G-2-N, the metabolites which contain a nitrate group in the central position, showed higher concentrations than the respective isomeric compounds. The combined glyceryl dinitrates reached concentrations between 10.2 and 21.7 ng/ml, the combined mononitrates varied from 70.4 to 106.8 ng/ml. The ratios of the areas under the curve G-1,3-DN:G-1,2-DN:G-1-N:G-2-N were 1:4:19:64, on average. Taking into consideration the relative vasodilator potencies of glyceryl nitrates in the animal, our results give rise to the hypothesis that the glyceryl dinitrate metabolites participate in the clinical efficacy of large oral doses of sustained release GTN.

[The pharmacology and pharmacokinetics of glycerol-2-nitrate]. / Untersuchungen zur Pharmakologie und Pharmakokinetik von Glycerol-2-nitrat.

Glyceryl 2-nitrate (G-2-N), which is the major metabolite of glyceryl trinitrate (GTN, Nitro Mack, glyceryl 1-nitrate (G-1-N) and isosorbide-5-nitrate (IS-5-N, Mono Mack) were examined in a comparative study. The haemodynamic and antianginal properties and the spasmolytic activity on blood vessels were investigated in the rat and dog. Also examined were the pharmacokinetics of G-2-N in the rat and of oral GTN in the dog. Strips of rat aorta contracted with potassium chloride or with norepinephrine were relaxed by G-2-N, but somewhat more weakly than with IS-5-N or G-1-N. After oral administration to the anaesthetized rat or to the conscious dog G-2-N exhibited antianginal and hypotensive activity for 6 h. The duration of action of orally administered GTN in the dog depended on the concentration used and was between 15 and 360 min. The half-life of elimination of G-2-N in the rat came to 2 h, and the substance was 100% bioavailable. The concentrations of G-2-N found in the walls of rat vena cava caudalis and rat aorta abdominalis were twice as high as those in blood or plasma. After oral administration of GTN to the conscious dog, G-2-N is the main metabolite, followed by G-1-N, glyceryl 1,2-dinitrate (1,2-GDN), and glyceryl 1,3-dinitrate (1,3-GDN). After a large oral dose of GTN (30 mg/kg), G-2-N contributes to the pharmacodynamic effect from the 3rd h or earlier.

Glyceryl-1-nitrate pharmacokinetics in healthy volunteers.

The plasma kinetics and urinary excretion of glyceryl-1-nitrate (G-1-N), a metabolite of glyceryl trinitrate with antianginal potential, were investigated in 10 healthy male volunteers, after intravenous infusion and oral administration of 20 mg G-1-N. The apparent volume of G-1-N distribution was 601 corresponding to 0.761 kg-1 body weight, on average. It is suggested that total body water is the principal biological correlate of the hydrophilic drug. Mean intravenous clearance was 283 ml min-1 or 3.61 ml min-1 kg-1. The average of elimination half-lives were 2.50 +/- 0.36 (s.d.) h after the intravenous and 2.54 +/- 0.40 (s.d.) h after the oral dose. Inter-subject variances of pharmacokinetic parameters were low compared to variances reported for glyceryl trinitrate. The coefficient of intra-subject variation of the elimination half-lives was 8.8%. 5.5% (i.v.) and 5.4% (p.o.) of the administered dose were excreted into urine up to 48 h after the administration. 1% (i.v.) and 1.5% (p.o.) were in the conjugated form. The oral dose was rapidly and almost completely absorbed. The oral bioavailability on the basis of areas under the curve amounted to 88.6% on the average. For clinical use, owing to its high oral bioavailability, long residence in the body, inactivation by metabolic conversion, and good predictability of kinetic parameters, G-1-N offers advantage over glyceryl trinitrate.

[Comparative hemodynamics action of glycero-2-nitrate and glycerol trinitrate in various species and the pharmacokinetics of glycerol-2-nitrate in the dog]. / Vergleichende hämodynamische Wirkung von Glycerol-2-nitrat und Glyceroltrinitrat an verschiedenen Tierarten und Pharmakokinetik von Glycerol-2-nitrat am Hund.

Comparative Hemodynamic Activity of Glyceryl 2-Nitrate and Glyceryl Trinitrate in Various Species and Pharmacokinetics of Glyceryl 2-Nitrate in Dog A single dose of glyceryl 2-nitrate (G-2-N) had practically identical hypotensive and cardiovascular activity when administered intravenously or enterally to the anaesthetized rabbit, cat or dog. In all three species the hypotensive and also cardiovascular activity of G-2-N lasted much longer than that of glyceryl trinitrate (GTN, Nitro Mack). In the rabbit, cat and dog enterally active doses of GTN were 500-1000 times greater than parenterally active doses. In all species enterally administered GTN was about 8 times more active than enterally administered G-2-N. G-2-N is 100% bioavailable in the conscious dog.

[Hypotensive, antianginal action and pharmacokinetics of glyceryl-1-nitrate in rats and dogs]. / Hypotensive, antianginöse Wirkung und Pharmakokinetik von Glycerol-1-nitrat an der Ratte und am Hund.

The antianginal and hypotensive activity and the pharmacokinetic properties of glyceryl 1-nitrate (G-1-N) were examined in the rat and in the dog. The level and duration of antianginal and hypotensive activity were the same after single or repeated oral dosage of G-1-N to the anaesthetized rat. The haemodynamic activity of intravenously administered G-1-N in the anaesthetized and thoracotomized dog was dose-dependent. A bolus injection of G-1-N or glyceryl trinitrate (GTN, Nitro Mack) antagonized the cardiovascular activity of intravenously injected dihydroergotamine (DHE) in the anaesthetized and thoracotomized dog. The bioavailability of G-1-N in the rat and in the dog is practically 100%. After intravenous or oral administration to the rat the concentrations of G-1-N in the walls of the vena cava caudalis were markedly higher and in the aorta abdominalis somewhat higher than in the blood or in the other organs examined. G-1-N was eliminated more slowly from the walls of the animals veins than from the walls of the aorta abdominalis or from the blood.

[Influence of antianginal drugs on Lypressin induced T-wave enhancement in the electrocardiogram of the rat]. / Einfluss antianginöser Substanzen auf die durch Lypressin induzierte T-Wellenerhöhung im EKG der Ratte.

Lypressin enhances the T-wave in the ECG of the anesthetized Sprague-Dawley rat and this has been used in screening for antianginal activity. After oral administration the durations of action of the organic nitrates, glyceryl trinitrate, isosorbide dinitrate, glyceryl 1,2-dinitrate, glyceryl 1,3-dinitrate and of SIN-1 (3-morpholinosydnonimine), molsidomine and nicorandil were shorter than those of verapamil and nifedipine. The sequence of the durations of action of the substances examined was the same in the rat as in man.

[Comparative pharmacology of glycerol-1-nitrate and glyceryl trinitrate in various species]. / Vergleichende Pharmakologie von Glycerol-1-nitrat und Glyceroltrinitrat an verschiedenen Tierarten.

The present studies yield that all 4 metabolites of glyceryl trinitrate (Nitro Mack, GTN) cause the same typical pharmacological effects as the parent substance. Continuous infusion of 4 mg/kg/min of glyceryl 1-nitrate (G-1-N) in the conscious dog results in a drop in blood pressure which is maintained for at least 20 min after stopping the infusion. Under comparable conditions the reduction in blood pressure caused by glyceryl 2-nitrate (G-2-N) (infused at 16 mg/kg/min) decreases by only 3 mmHg. The drop in blood pressure caused by a continuous infusion with GTN (8 micrograms/kg/min) disappeared 10 to 12 min after the end of the infusion. GTN is active in rat, dog and man for 15 to 30 min. Our experiments indicate that after oral administration to the rat or dog glyceryl 1,2-dinitrate (1,2-GDN) and glyceryl 1,3-dinitrate (1,2-GDN) are active for 3 h. Earlier experiments have shown that the administration of high oral doses of 1,2-GDN or 1,3-GDN (280 mg/kg) to the rat increases the time of action to 5-6 h. This is taken as indication that the dinitrates form pharmacologically active metabolites. 1,3-GDN (70 mg/kg p.o.) and 1,2-GDN (140 mg/kg p.o.) exhibited antianginal activity in the rat for 3 or 2 h, respectively. Orally administered GTN is only active for 15 min in the rat or dog. Its pharmacological activity after this time and up to 2-3 h on the rat (280 mg/kg p.o.) and on the dog (4 mg/kg p.o.) is brought about by the dinitrate metabolites (1,2-GDN, 1,3-GDN) and after this time probably only by G-1-N.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of activated charcoal on the bioavailability of piroxicam in man.

The effect of single and multiple oral doses of activated charcoal (a.c.) on the plasma concentrations of piroxicam was investigated in a cross-over study in 6 healthy volunteers after oral and rectal doses of 20 mg piroxicam. 50 g a.c. swallowed 5 min after the oral administration of one capsule of piroxicam almost completely prevented the absorption of the drug. 70 g a.c. per day were given in multiple doses over the interval of 10-58 h after the oral and 2-58 h after the rectal administration of piroxicam. This treatment reduced the mean bioavailability of piroxicam by 41.7% (oral) or 48.8% (rectal), relative to the control. The apparent total clearance increased significantly (p less than 0.05) to 163.6% (oral) or 187.9% (rectal) of the control. Half-lives of elimination were reduced on the average from 40.2 h to 19.6 h after the oral dose and from 40.7 h to 21.6 hours after the rectal dose under the a.c. treatment. It is inferred from these results that piroxicam is subject to enteral circulation. A.c. appears useful as an antidote in acute intoxications from piroxicam.

Pharmacokinetics of oral glycerol-1-nitrate.

The plasma kinetics and urinary excretion of glycerol-1-nitrate (G-1-N), a water soluble metabolite of glycerol trinitrate with anti-anginal potential, have been investigated in healthy human volunteers following oral doses of 10, 20 and 40 mg tablets and 20 mg as drops. In all volunteers G-1-N was rapidly absorbed. The mean concentration-time curves peaked 40 min after administration of tablets at 144 ng/ml (10 mg), 308 ng/ml (20 mg) and 573 ng/ml (40 mg). After the drops the peak of 324 ng/ml occurred at 1 h. The areas under the G-1-N concentration-time curve and the G-1-N peak heights were linear with dose. Tablets and drops can be regarded as bioequivalent with respect to area under the curve and elimination half-life. The bioavailability of the 20 mg tablet relative to the 20 mg drops was 98.6% in terms of area under the curve. The mean apparent half-life of G-1-N elimination from plasma was 2.69 +/- 0.67 h (n = 46). The mean residence time of G-1-N in the body was 4.65 h compared to 0.28 h for glycerol trinitrate after buccal administration. Female volunteers were found to have significantly lower areas under the curve than male volunteers. The difference was probably due to differences in body weight. Renal excretion does not play an important role in the elimination of oral G-1-N from the body. An overall average of 5.42% of the G-1-N dose was excreted in the urine; free drug accounted for 4.02% and conjugated drug for 1.40%.

Preliminary study of the pharmacokinetics of desmethyldiazepam administered as drops or tablets.

Desmethyldiazepam (Vegesan) was administered in the form of 5-mg and 10-mg tablets and of 10-mg drops to 4 male and 4 female young healthy volunteers. The plasma levels of desmethyldiazepam were measured over 168 h. The time courses could be fitted to the one- or to the two-compartment model. The mean half-lives of elimination came to 75.3 +/- 32.0 (SD) h (5-mg tablets), 66.5 +/- 21.0 (SD) h (10-mg tablets) and 78.4 +/- 33.2 (SD) h (10-mg drops). The bioavailability of desmethyldiazepam from tablets and from drops was practically the same. The bioavailability appeared to be independent of dose in this range. A significantly higher total plasma clearance was calculated for the male than for the female volunteers after all three dosage forms (p less than 0.05). The total plasma clearance lay between 4.8 and 13.0 ml/min for the female and 12.4 and 24.3 ml/min for the male volunteers. Ingestion of the contraceptive pill is suggested as a possible cause of the sex differences.