Pharmacokinetics of tramadol in children after i.v. or caudal epidural administration.

We have studied the pharmacokinetics of a single bolus dose of tramadol 2 mg kg-1 injected either i.v. or into the caudal epidural space in 14 healthy children, aged 1-12 yr, undergoing elective limb, urogenital or thoracic surgery. Serum concentrations of tramadol and its metabolite O-demethyl tramadol (MI) were measured in venous blood samples at various intervals up to 20 h by non-stereoselective gas chromatography with nitrogen-selective detection. All pharmacokinetic variables were evaluated using a non-compartmental model. After a single i.v. injection (n = 9), the mean elimination half-life of tramadol was 6.4 (SD 2.7) h, with a volume of distribution of 3.1 (1.1) litre kg-1 and total plasma clearance of 6.1 (2.5) ml kg-1 min-1. All of these pharmacokinetic variables were similar to those reported previously in adults. After caudal epidural administration (n = 5), mean elimination half-life was 3.7 (0.9) h, volume of distribution was 2.0 (0.4) litre kg-1 and total clearance was 6.6 (1.9) ml kg-1 min-1. The caudal/i.v. quotient of the AUC was 0.83, which confirms that there is extensive systemic absorption of tramadol after caudal administration. Serum concentrations of MI showed a time course typical of a metabolite after both modes of administration. Serum concentrations of MI after caudal administration were lower than those after i.v. injection.

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 4th communication: drops (without ethanol).

In a balanced two-period cross-over study with 12 (6 male, 6 female) healthy young subjects the pharmacokinetics and absolute bioavailability of tramadol (tramadol hydrochloride, CAS 36282-47-0) after oral administration of Tramal drops (without ethanol) were to be determined in comparison with a 30-min i.v. infusion. Each fasting volunteer received the two single doses of 50 mg tramadol-HCl each in the morning; the time interval between the administrations was one week. Serum and urine concentrations of tramadol were analysed by gas chromatography. The pharmacokinetic evaluation was carried out model-dependently after previous selection of the optimal model by means of the Akaike information criterion; solely the extent of bioavailability was calculated model-independently. The study population results were presented descriptively as geometric means with standard deviation [xg (SDg)] or as medians with range [x (min, max)]. Model-dependently and model-independently calculated areas under the serum concentration curves (AUC and AUC, resp.) differed only minimally. The extent of the absolute bioavailability (F) of tramadol in the drops, based on AUC data, was 70.6 (1.13)% with a 90% confidence interval of 65.9-75.6% (ANOVAlog). The p.o. serum concentration peaks were reached after tmax = 1.2 (0.74, 1.5) h and amounted to Cmax = 136 (1.33) ng/ml, the half-life of absorption was t1/2,ka = 0.23 (1.89) h and the lag time t0 = 0.23 (0.20, 0.49) h. The dose-normalised p.o. and i.v. results for all pharmacokinetic parameters agreed well with those of a previous study with ethanol-containing drops. In summary, it may be concluded that the active ingredient is rapidly absorbed after oral administration of the drops without ethanol. Rate and extent of the absolute bioavailability of tramadol in drops without ethanol were about the same as after administration of drops with ethanol. The results of this study gave no indication of a therapeutically relevant gender difference in the pharmacokinetics of tramadol.

Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion.

OBJECTIVES AND METHODS: The bioavailability of tramadol after i.m. injection of tramadol-HCl was determined from serum concentration data in a balanced two-period crossover study with 12 healthy male subjects in comparison to the 30-min i.v. infusion. Additionally, the tramadol concentrations in saliva and urine samples were measured. The subjects received single doses of 50 mg after an overnight fast, the washout period was one week. Serum, saliva and urine concentrations of tramadol were analyzed by gas chromatography, and pharmacokinetic (PK) evaluation was carried out model-independently. Descriptive statistical evaluation was performed by calculating geometric means with standard deviations (x(g) (SDg)) or medians with ranges (x (min, max)) and the extent of systemic availability (F) was tested for bioequivalence using the ANOVAlog-based 90% confidence interval (CI). RESULTS: Retrospective sparteine phenotyping revealed two of the subjects as poor metabolizers (PM). Nevertheless, all subjects were considered on statistical evaluation since the PM results were within the range of the extensive metabolizers (EM). The 90% CI of F = AUCi.m./AUCi.v. was 92.9 - 105.4% (x(g) = 99.0%) and was thus within the range of 80 - 125% generally accepted for a positive bioequivalence decision. After i.m. injection the serum concentration peaks were reached after t(max) = 0.75 (0.25, 1.50) h and amounted to c(max) = 166 (1.24) ng/ml; the corresponding results after i.v. infusion were t(max) = 0.50 (0.33, 1.50) h and c(max) = 293 (1.35) ng/ml. Thus, the results reflect the different invasion kinetics of the two modes of administration. However, the observed difference is not therapeutically relevant since in both cases minimal effective serum concentrations are already reached after a few minutes and are maintained for 9 - 10 h on the average. The i.v. results for all PK parameters agreed well with those of previous studies. Tramadol concentrations in saliva and urine were considerably higher than in serum. Therefore, saliva and urine samples are very suitable for the qualitative proof of tramadol intake in therapeutic drug monitoring and forensic toxicology. CONCLUSIONS: Tramadol is rapidly and almost completely absorbed after i.m. injection. The i.m. injection and the 30-min i.v. infusion are bioequivalent with respect to the extent of systemic availability. The differences in the times of onset and duration of action to be expected due to a slightly slower invasion after i.m. injection are small and probably therapeutically irrelevant.

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories.

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after rectal administration of tramadol suppositories (Tramal) were determined in a balanced crossover study in 10 female volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one rectally (1 suppository) and one intravenously (2 ml of a solution for injection). The formulations were administered in the morning, the washout period was one week. Serum concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability was calculated model-independently. The extent of the absolute bioavailability (F) of tramadol in the suppositories, based on AUC data, was 77.0% (point estimate; n = 10) with a 95% confidence interval of 70.8-83.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2933 +/- 304 h.ng/ml (rectal) and 3775 +/- 446 h.ng/ml (i.v.) [mean +/- SD; n = 10]. Optimal curve fitting of the serum concentration data after rectal administration presupposed the existence of two absorption sites with different absorption rates and lag times. Under this premise the absorption half-lives were t1/2,ka;1 = 1.7 h (median; range: 1.1-3.1 h) and t1/2,ka;2 = 0.98 h (0.35-1.9 h), and the corresponding lag times were t0;1 = 0 h (0-0.37 h) and t0;2 = 0.66 h (0.31-3.5 h). The relative portion of the more rapidly absorbed quantity of tramadol varied between 9.2 and 50% (median: 28%). The maxima of the serum concentration curves were reached 2-6 h after rectal administration; the means of the individual maxima were 294 +/- 50 ng/ml (Cmax) and 3.3 +/- 1.3 h (tmax). There were large differences in the distribution rate between the volunteers. The means of the half-life of the slower distribution (t1/2, alpha) were 1.38 +/- 0.47 h (rectal; n = 10) and 1.78 +/- 0.63 h (i.v.; n = 7). In the terminal phase the biological half-life (t1/2, beta) was 5.7 +/- 1.0 h (rectal) and 5.7 +/- 0.9 h (i.v.), respectively. The values determined after i.v. injection for the total distribution volume and the total clearance were 216 +/- 231 (Vd, beta) and 447 +/- 56 ml/min (Cltot). The results show that after rectal administration of the tramadol suppositories the absorption of the active ingredient is rapid enough for therapeutic purposes and that the extent of the absolute bioavailability is higher than after oral administration of tramadol-HCl, probably due to a reduced first-pass metabolisation after rectal administration.

Pharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 2nd communication: drops with ethanol.

The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after oral administration of Tramal drops (with ethanol) were determined in a balanced cross-over study in 8 (4 male and 4 female) volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one by oral (1 ml of drops) and one by intravenous route (2 ml of a solution for injection). The formulations were administered in the morning; the washout period was one week. Serum and urine concentrations of tramadol-HCl were determined by gas chromatography-mass spectrometry and gas chromatography, respectively, and the pharmacokinetic evaluation was carried out model-dependently. Only the extent of bioavailability and the renal clearance were calculated model-independently. The extent of the absolute bioavailability (F) of tramadol after oral administration of the drops, based on AUC data, was 66.3% (point estimate; n = 8) with a 95% confidence interval of 58.1-75.6% (ANOVAlog). The areas under the serum concentration curves of tramadol-HCl calculated by curve fitting (AUC), which agreed very well with the model-independently determined areas (AUC), were 2390 +/- 712 h.ng/ml (p.o.) and 3490 +/- 510 h.ng/ml (i.v.) (mean +/- SD; n = 8). After oral administration the means of the serum concentration peaks were 308 +/- 89 ng/ml (cmax) and 1.20 +/- 0.39 h (tmax), the half-life of absorption was 0.34 +/- 0.18 h (t1/2,ka) and the lag time 0.23 +/- 0.01 h (t0). The biological half-life in the terminal phase (t1/2,beta) was 5.5 +/- 0.9 h and agreed well with the value of 5.2 +/- 0.8 h determined after i.v. injection. There were large differences between the volunteers in the distribution rate. For the slower distribution half-life (t1/2,alpha) mean values of 1.2 +/- 0.7 h (p.o.; n = 6) and 1.9 +/- 0.7 h (i.v.; n = 6) were obtained. The values determined after i.v. injection for the total distribution volume and the total and renal clearance were 216 +/- 21 l (Vd,beta), 487 +/- 71 ml/min (Cltot) and 77 +/- 20 ml/min (Clren), respectively. These results show that after administration of the drops (with ethanol) the active ingredient tramadol is rapidly absorbed and that the extent of the absolute bioavailability is about the same as after oral administration of tramadol capsules.

Bioavailability of enteral tramadol formulations. 1st communication: capsules.

The absolute bioavailability of tramadol hydrochloride (rac-1(e)-(m-methoxyphenyl)-2-(e)-(dimethylaminomethyl)cyclohexan- 1(a)-ol hydrochloride, CG 315) after the oral administration of Tramal capsules was determined in a balanced cross-over study in 10 male volunteers. Each volunteer received two single doses of 100 mg tramadol hydrochloride, one by oral (2 Tramal capsules) and one by intravenous route (2 ampoules of Tramal 50 solution for injection). The formulations were administered in the morning on an empty stomach, and the interval between the two applications was one week. Serum concentrations of tramadol were determined by gas chromatography-mass spectrometry and the bioavailability was ascertained by calculation of the areas under the serum concentration curves. The absolute bioavailability of tramadol in Tramal capsules was 68 +/- 13% (means +/- SD; n = 10) with a range of 41-84% and a 95% confidence interval of 55.0-79.2%. The areas under the serum concentration curves of tramadol hydrochloride (AUC) were 2488 +/- 774 ng X h/ml (p.o.) and 3709 +/- 977 ng X h/ml (i.v.). Peak serum concentrations of 280 +/- 49 ng/ml were reached 2 h after oral administration of two Tramal capsules; a serum concentration of 100 ng/ml (assumed as the threshold value for analgesic efficacy) was reached after 0.68 +/- 0.17 h and was maintained for 9.0 +/- 2.2 h. The half-life of absorption was 0.38 +/- 0.18 h and the lag-time 0.48 +/- 0.14 h. In the terminal phase the biological half-lives of tramadol were 5.1 +/- 0.8 h (p.o.) and 5.2 +/- 0.8 h (i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of tramadol in human serum by capillary gas chromatography with nitrogen-selective detection.

A specific, sensitive and precise method for the determination of tramadol in human serum is described. It comprises a three-step extraction procedure and a specific determination by capillary gas chromatography with nitrogen-selective detection, using a homologue of tramadol as an internal standard. The specificity of the method was checked by gas chromatography-mass spectrometry. Precision parameters were 1.7-5.5% (within-run) and 3.2-5.7% (between-run) in the concentration range 12.5-200 ng/ml. The detection limit was about 3 ng/ml.

Quantitative determination of tramadol in human serum by gas chromatography-mass spectrometry.

A gas chromatographic-mass spectrometric method for the quantitative determination of tramadol in human serum, plasma or whole blood samples is described. The method involves the use of [2H2, 15N]tramadol hydrochloride as an internal standard and chemical ionization with isobutane, employing single-ion monitoring for quantification. It is specific, sensitive and precise, and has high accuracy. The within-run coefficient of variation is about 1% between 25 and 200 ng/ml and 1.8-2.9% at the lowest concentrations tested (6.25 and 12.5 ng/ml). The between-run coefficient of variation increases from 1.6% to 5.2% with decreasing concentration from 200 to 12.5 ng/ml. The calibration graphs were linear in the tested concentration range, and the accuracy of the assay was not dependent on the sample volume used. The detection limit was about 4 ng/ml for serum samples of 1 ml. The method proved suitable for pharmacokinetic studies. Its high sensitivity allows measurements of serum concentrations for at least 30 h after the single administration of therapeutic doses of tramadol hydrochloride.

Pharmacokinetic considerations for the setting of in-vitro models.

Nearly all in-vitro kinetic models hitherto employed only consider serum concentration curves of the antibiotic. Data thus obtained at best reflect the situation in septicaemia. However, they are not applicable for infections where infecting bacteria are not localized within the blood. This paper presents a method for calculating the time course of the non-protein bound drug in tissue water. The concept makes use of serum concentration curves, the extent of serum protein binding and the peak time of total drug concentration in the tissue. This is practicable since all data necessary for calculation are available experimentally. Using cefmenoxime, cefotaxime, latamoxef (moxalactam) and ceftriaxone as examples, the vast differences between the total concentration of the antibiotic in serum and the concentration of the non-protein bound antibiotic in the tissue water are demonstrated. Therefore, only the results of in-vitro experiments, which are based on time courses of the non-protein bound drug in the tissue water, are considered relevant for assessing therapeutic efficacy of an antibiotic.

[Bioavailability of penicillin V in aqueous dosage forms]. / Bioverfügbarkeit von Penicillin V in einer wässrigen Zubereitungsform.

The bioavailability of Megacillin-oral-Trockensaft (active substance: potassium salt of phenoxymethylpenicillin, penicillin V potassium) was compared with that of another commercially available drug containing the same active substance. In a cross-over study, 12 healthy volunteers were administered by oral route 10 ml of each preparation (equivalent to 600 000 U = 392.2 mg potassium salt of phenoxymethylpenicillin) under standardized experimental procedure. Relative bioavailability was assessed by determination of phenoxymethylpenicillin concentrations in the plasma, employing both microbiological assay as well as high-performance liquid chromatography, by computation of the areas under the plasma concentration curves, and by calculation of the time periods necessary for the attainment of maximum plasma concentrations. In order to assess differences between the two forms in duration of efficacy, calculation of time intervals were based on plasma concentrations which were above 0.5; 1.0 or 1.5 micrograms/ml, respectively. Results of this comparative study indicate that Megacillin-oral-Trockensaft is superior to the other commercial preparation. The considerably better bioavailability of Megacillin-oral-Trockensaft is attributed to a substantially higher absorption rate and to a 2.4 times greater extent of absorption. Due to the distinct advantage in the bioavailability of Megacillin-oral-Trockensaft peak plasma concentrations of phenoxymethylpenicillin 5-6 fold higher and are reached faster when compared with those following intake of the other form tested. In practice, the superior bioavailability of Megacillin-oral-Trockensaft guarantees quicker initiation of therapeutic activity and greater safety (higher plasma concentrations, prolonged effect).

Role of renin release in the hemodynamic, renal and dipsogenic actions of the prostacyclin analogue CG 4203 in conscious rats.

The influence of CG 4203, a chemically and metabolically stable prostacyclin analogue, on plasma renin activity, arterial blood pressure, renal function and water intake was investigated in conscious rats. CG 4203 infused intravenously starting at 1 microgram X kg-1 X min-1 induced both a fall in blood pressure and an increase of plasma renin activity. The angiotensin II antagonist saralasine infused simultaneously intensified the hypotensive effect of CG 4203 (1.0 microgram X kg-1 X min-1). Within a similar dose range CG 4203 dose-dependently inhibited diuresis and saluresis and reduced the urinary sodium/potassium ratio. These effects were partially reversed by adrenalectomy and completely abolished by pretreatment with the angiotensin I converting enzyme inhibitor captopril. Similarly, CG 4203 (0.21 - 4.64 micrograms X kg-1 X min-1) dose-dependently caused increased water intake which was prevented by previous nephrectomy. In conclusion, it is demonstrated that CG 4203 like prostacyclin itself already at hypotensive threshold dosages stimulates a functionally relevant renin release. The activation of the renin-angiotensin-aldosterone system attenuates the intrinsic hypotensive effects of CG 4203. the antidiuretic and dipsogenic efficacy of CG 4203 can also be attributed to renin-dependent angiotensin II formation.

Designing prostacyclin analogues.

A series of prostacyclin analogues were synthesized and investigated for influence on blood pressure in rats, in vivo inhibition of platelet aggregation in rats, and in vitro inhibition of platelet aggregation in human platelet-rich plasma. The common feature of the analogues described is a replacement of C1-C4 of prostacyclin by a carboxyphenylene residue. The following structure-activity relationships were obtained. Only the meta-carboxyphenylene derivatives yield substantial prostacyclin activity. The 2,3,4-trinor-1,5-inter-m-phenylene prostacyclin analogues in contrast to the natural prototype are reasonably stable against hydrolysis of the enolether bond. The corresponding 2,3,4-trinor-1,5-inter-m-phenylene analogues of carbaprostacyclin have a somewhat lower specific activity but are superior in stability at acid pH values. With regard to the stereoisomerism at the delta 5 double bond, the Z-isomers of the oxa-cyclic prostacyclin series and the E-isomers of the carba-cyclic prostacyclin series are substantially more active than their counterparts. As with natural prostacyclin, the OH group at C15 has to be present in S-configuration. The "wrong" isomers do not inhibit prostacyclin-dependent effects. Resistance against 15-hydroxyprostaglandin dehydrogenase is achieved by substitutions at or near C15. Optimum specific activity combined with resistance against all known prostaglandin-activating enzymes is observed in prostacyclin and carbaprostacyclin analogues, in which the terminal n-pentyl residue is replaced by cyclohexyl. Duration of action, i.e. lowering of blood pressure in anaesthesized rats and inhibition of platelet aggregation in anaesthesized rats, was investigated with selected analogues in order to check the consequences of chemical and metabolic stabilization.(ABSTRACT TRUNCATED AT 250 WORDS)

[Biotransformation of tramadol in man and animal (author's transl)]. / Metabolismus von Tramadol bei Mensch und Tier.

Following p.o. administration of 14C-labelled rac.-1-(e)-(m-methoxyphenyl)-2-(e)-dimethylaminomethyl-cyclohexan-1-(a)-ol hydrochloride (tramadol hydrochloride, CG 315, Tramal) to mice, hamsters, rats, guinea pigs, rabbits, dogs and man the metabolic pathways were investigated and the results compared. After synthesis of the reference substances the metabolites were identified by co-chromatography using both TLC (thin-layer chromatography) and HPLC (high-performance liquid chromatography) methods, by co-crystallization and by gas chromatography-mass spectrometry. In all species the main metabolic pathways are N- and O-demethylation (phase I reactions) and conjugation of O-demethylated compounds (phase II reactions). 11 metabolites are known, 5 arising by phase I reactions (M1 to M5) and 6 by phase II reactions (glucuronides and sulfates of M1, M4 and M5). The 5 phase I metabolites are mono-O-demethyl-tramadol (M1), mono-N-demethyl-tramadol (M2), di-N-demethyl-tramadol (M3), tri-N,O-demethyl-tramadol (M4) and di-N,O-demethyl-tramadol (M5). The biotransformation scheme of tramadol is qualitatively identical in man, dog, rabbit, guinea pig, rat, hamster and mouse. In all species M1 and M1-conjugates, M5 and M5-conjugates and M2 are the main metabolites, whereas M3, M4 and M4-conjugates were only formed in minor quantities. Following p.o. administration to man and animals 14C-tramadol are rapidly and almost completely absorbed. The unchanged drug and metabolites are mainly excreted via kidneys. The cumulative renal excretion of total radioactivity accounts for approximately 90% in man and varies from 86 to 100% in mouse, hamster, rat, guinea pig, rabbit and dog; the residual of the applied radioactivity appears in the feces. Apparently tramadol is metabolized much more rapidly in animals than in man. For that reason there are appreciable differences between man and animals in the amount of tramadol excreted unchanged in the urine (about 30% and 1% of the p.o. dose, respectively). After incubation with beta-glucuronidase and arylsulfatase at least 81% of the excreted radioactivity could be extracted from the urine of man animals (with the exception of the guinea pig and the rabbit). In man all extractable metabolites were identified.

[Distribution and excretion of 14c-butylbiguanide in man (author's transl)]. / Verteilung und Ausscheidung von 14C-Butylbiguanid beim Menschen.

Seven patients suffering from maturity on-set diabetes mellitus were given orally 100 mg of 14C-labelled butylbiguanide, specific activity 1.40 or 1.23 muCi/mg, resp. Three days before oral administration, two of the patients had received an i.v. injection of 50 mg butylbiguanide labelled with 120 muCi 14C. The radioactivity in the blood of the patients was followed up during the first 12-h period after administration of the drug. For determination of the radioactivity in the urine aliquots of three 24-h portions were measured. Furthermore, the radioactivity was checked of each individual sample of faeces for the first 72 h after administration. The radioactivity in the exhaled air was also measured. By comparison of the excretion after i.v. and oral application an absorption efficiency of 90% to 92% was calculated. Butylbiguanide is almost exclusively and fast excreted via the kidney. 86.5% of the i.v. administered material was eliminated within 24 h and 88.1% within 3 d in the urine of a person without kidney disease. Elimination through faeces was negligible, 0.2% in a person without kidney disease and 0.7% in a patient with renal insufficiency. The data obtained from the exhaled air show that there is only a negligible break-down of butylbiguanide, if any, to CO2 in man.