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Falipamil (2-[3-[3-(3,4-dimethoxyphenetylmethylamino]propyl]-5,6- dimethoxyphthalamidine; 1) is a new specific bradycardic agent for the treatment of sinus tachycardia. Pharmacokinetics of falipamil in humans (n = 6) was determined in plasma and urine after iv administration of 100 mg (1.85 MBq) per person of 14C-labeled drug by liquid scintillation counting and by a specific, sensitive reversed-phase totally automated HPLC system with fluorimetric detection. Recovery of total radioactivity was 91.8 +/- 3.7%, with 68.2 +/- 4.3% in urine and 23.6 +/- 2.5% in the feces. The majority of radioactivity was excreted within 24 to 48 h. The parent drug, falipamil (1), and its N-desmethyl-metabolite (2), which is approximately 100 times less active than 1, contributed 14.1 +/- 1.6 and 4.5 +/- 0.7%, respectively, of the dose to urinary excretion. Plasma protein binding of 1 and 2 was 87.9 +/- 1.2 (concentration range: 2000-8000 ng/mL) and 89.7 +/- 0.5% (concentration range: 62.5-1000 ng/mL), respectively. Plasma concentrations of 1 peaked at 2 min at 724 +/- 173 ng/mL, declined biphasically, and were fitted to a two-compartment open model. Plasma concentrations of 2 were very low, in all cases ranging from 0 to 35 ng/mL. The dominant terminal half-life (beta-phase) of 1 from plasma was 1.8 +/- 0.6 h (range 1.4-2.9 h), mean residence time was 2.4 +/- 0.4 h, total body clearance was 1108.5 +/- 119 mL/min, and renal clearance was 117 +/- 20 mL/min. All parameters demonstrated very low intersubject variability.

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On the basis of approximately 60 publications and in view of our own results we present a comprehensive review as to the mode of action, the pharmacokinetics, the metabolism and the toxicology of 8-methoxypsoralen (8-MOP) and its consequences in the PUVA therapy of psoriasis. The interaction of 8-MOP with DNA is presently considered to be the most likely mode of action. 8-MOP is subject to strong first-pass effects with considerable individual variations in plasma levels. An exact timing of drug dose and light dose is essential for a successful therapy, simultaneously minimizing the potential short-term and long-term risks of PUVA therapy.

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Bromhexine (N-methyl-N-cyclohexyl-(2-amino-3,5-dibromobenzyl)-ammoniumhydr ochloride) forms N-nitroso-N-methyl-N-cyclohexylamine (NMCA) under the conditions of the WHO Nitrosation Assay Procedure (NAP-test). The formation kinetics of this compound was investigated. The formation of NMCA depends on the square of the nitrite concentration. The reaction has a narrow pH-optimum at pH 3. The reaction is quick: After 1 h about 70% of the maximum amount of NMCA is formed. To study this reaction kinetics sensitive assays with a detection limit up to 0.5 ng/ml NMCA were developed. The stability of the components of the system, especially that of NMCA and nitrite, were further studied. The latter is rather instable under conditions found in an acidic stomach.

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The possible formation of N-nitroso-N-methyl-N-cyclohexylamine (NMCA) from the drug bromhexine (N-methyl-N-cyclohexyl-(2-amino-3,5-dibromobenzyl)-ammonium hydrochloride) and nitrite was investigated in humans using three different approaches: 1. analysis on metabolites of NMCA in human urine; 2. analysis on NMCA in human gastric juice; 3. in vitro incubation of human gastric juice with therapeutic bromhexine doses. Diet given to volunteers was varied during these investigations with respect to nitrate content. Experiments with a maximum load of 200 mg nitrate to stimulate nitrite formation were performed. Results of in vivo experiments did not indicate any formation of NMCA. In one out of 39 ex-vivo/in-vitro experiments (with a load of 100 mg nitrate in drinking water) 0.5 ng NMCA/ml gastric juice could be detected which is near the detection limit. Finally, this study showed that bromhexine is not secreted by saliva. This allows to conclude that nitrite and bromhexine do not reach the stomach simultaneously over a longer period of time. In consequence, medication with bromhexine is not regarded to represent a risk due to nitrosamine formation.

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We discovered a strong but saturable first-pass effect after oral administration of psoralens by using different doses and simultaneous or timed application of stable isotopes. Therefore, small variations of dose, disintegration of drug, and amount and rate of absorption gave rise to great differences in plasma levels and therapeutic efficacy. For practical therapy, the following conclusions can be drawn: 1) Galenical forms of psoralens should ensure a quick and highly reproducible absorption. 2) In the event that inefficacy has been detected, plasma levels should be determined, and the psoralen dosage should be increased rather than the irradiation doses in most instances. 3) For oral psoralen and 320- to 400-nm UV (UVA) treatment, a combination of 5-methoxypsoralen (5-MOP) and 8-MOP (with a lower dose and either administered 30 minutes later than the 5-MOP or in a drug product with quick release of 5-MOP and quick but delayed release of 8-MOP) results in much higher efficacy and reproducibility. Therefore, compared with the single drug, in the combination, dose of drug and the amount of irradiation can be reduced considerably which may result in increased safety. 4) Plasma levels after oral administration of dissolved 4,5',8-trimethylpsoralen are low, but phototoxicity is comparable to that of the 5-MOP and 8-MOP.

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Proper oral PUVA therapy includes the application of a psoralen drug and the administration of light, and both of these have to be adjusted to each other in regard to dose and timing. As psoralens are rather insoluble, it is difficult to produce pharmaceutical formulations which ensure safe and predictable absorption. A strong, saturable first pass effect occurs after oral intake of psoralens, resulting in a wide variability in plasma levels and thus also in phototoxicity. Phototoxicity seems to be slightly delayed compared to plasma levels in the absorption phase, but then persists much longer than plasma levels. Therefore irradiation should be done at or shortly after tmax of plasma levels. "Skin levels" seem to parallel plasma levels rather than the time course of cutaneous photosensitivity, which indicates that they do not represent drug concentration at the true site of action. Metabolism and first pass of TMP are very fast and thus oral intake does not result in significant plasma levels. Phototoxicity may, however, occur if TMP is administered as a solution. The present paper discusses clinically relevant aspects of psoralen drug pharmacokinetics, including absorption, distribution, metabolism and excretion. The shortcomings in the development of regimens for oral psoralen photochemotherapy are pointed out, and suggestions for further developments are given. Based on the pharmacokinetic data, recommendations are given for an improved performance of clinical psoralen photochemotherapy.

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A specific, sensitive method for the determination of bromhexine in human plasma is described. It comprises a selective extraction procedure and a specific determination with capillary gas--liquid chromatography and nitrogen-selective flame ionization detection. The detection limit of the assay is about 0.5 ng/ml. The specificity of the assay was checked by gas chromatography--mass spectrometry. The method is applied to the pharmacokinetics of bromhexine in humans.

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A new fully automated high-performance liquid chromatography is described which detects drugs from directly injected plasma (urine, saliva) without sample pretreatment. The apparatus consists of a programmable automatic sampling unit, which is connected via two alternating working pre-columns to an analytical column ("alternating pre-column sample enrichment"). The new device is able to operate with directly injected body fluids like an auto-analyzer and is especially useful for pharmacokinetic and clinical studies, where drug concentrations have to be determined from plasma, urine or saliva.

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The plasma level course and the elimination of oxazepam (Adumbran) via urine were investigated following multiple oral administration in volunteers and patients with chronic renal failure. Additionally, drug metabolizing enzyme systems had been induced in the volunteers by pretreatment with phenobarbital. The plasma protein binding in vitro of oxazepam was determined in volunteers and patients. The plasma levels and the renal elimination of oxazepam and its metabolites do not show any differences between the two groups of volunteers (oxazepam and oxazepam after pretreatment). 83--92% of the dosage are eliminated via urine. In comparison, the plasma levels of oxazepam in patients with renal failure are half those of the volunteers. However, the plasma levels of oxazepam metabolites in patients are much higher than in volunteers and these increases correlate to the creatinine clearance of the patients. The non-protein bound oxazepam in plasma was found to be twice as high in the plasma of patients as that of volunteers. As a consequence, the lower plasma level of oxazepam in patients will be compensated for so that the pharmacological activity in patients and volunteers due to free oxazepam in the plasma water is nearly the same. Therefore a new dosage regimen for treatment with oxazepam in patients with renal failure is not necessary.

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Methoxsalen, administered orally shows a strong, albeit saturable first-pass effect, as demonstrated by classical dose linearity testing and by a new method, using stable isotopes and gas chromatographic mass spectrometric analysis. The therapeutic consequences of the first-pass effect are discussed.

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A sensitive and specific colorimetric assay for paracetamol (acetaminophen) in plasma is described. After a selective column extraction (Extrelut) and hydrolysis, paracetamol is determined by the (modified) Axelrod and Brodie procedure. The whole processing is performed in a centrifuge tube. This method yields a high recovery (90%), saves time and only 1 ml of plasma is needed. Due to low blank values, the limit of detection is as low as 0.2 microgram/ml. At a concentration of 10 and 2 microgram/ml the coefficient of variation is 4% and 10%, respectively. In contrast to the often used extraction method, no emulsions are formed with this column procedure. One person is able to perform 50 analysis per day.

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8-Methoxypsoralen is metabolized rapidly and completely in man. Most of the metabolites presently known have their origin in a metabolic attack on the furan moiety yielding an aryl-diol and aryl-acetic-acid and are excreted as conjugates.

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This paper gives a brief review of the pharmacokinetic studies performed on pirenzepine (L S 519 Cl2, Gastrozepin hitherto. Particular attention will be paid thereby to the clinical significance of the pharmacokinetic parameters.

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Following oral administration of 14C labelled 8-methoxypsoralen (8-MOP) in man the plasma level course, the metabolite-patterns and the elimination of the parent compound and its metabolites have been investigated. Additionally the results discovered have been compared with the data of pharmacokinetics on dog and rat. In man and rat the plasma protein binding of 8-MOP has been determined. Maximal levels of the total radioactivity in the plasma were achieved 2 h after dosing. At this time 8-MOP represents 50% of the radioactivity in the plasma. The plasma protein binding in vitro of 14C 8-MOP valued from 88% to 91% in man, and between 75% and 83% in the rat. Urinary elimination of the total radioactivity as a measure of the extent of absorption varies greatly and depends on the therapeutic formulation being employed. Following the administration of the solution 74% is recovered within 48 h. Faecal elimination of the total radioactivity reached 14% within 3 days. The metabolite-pattern does not show the unchanged 14C 8-MOP. Several polar metabolites occur in the urine among which biochemical conjugates have been recognized. Only polar metabolites are observable in the faeces from which the radioactivity is incompletely extractable. From a comparison of the metabolite profiles, the rat as well as the dog seem to be a useful animal species for experimental investigations with 8-MOP.

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Some possible reasons are discussed which may lead to changes in the pharmacokinetics of a drug during long-term toxicity tests. Since most of these alterations have toxicological consequences, their evaluation can be helpful in the interpretation of toxicity studies. Furthermore, and altered pharmacokinetic profile may be a diagnostic tool for the detection of organ damage (e.g., eliminatory organs). In this paper three examples of the "radioactive test dose method" are shown. This method allows a direct comparison of the pharmacokinetics between pretreated animals and controls by administration of a single radioactive test dose to both groups.

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Pharmacokinetics and biotransformation of trans-4-(2-amino-3,5-dibromo-benzylamino)cyclohexanol hydrochloride (ambroxol, NA 872 Cl) was studied using the 14C-labelled compound. Absorption after oral administration was found to be fast and complete. Elimination half-life of radioactivity in the blood was estimated as 20--25 h in rat, dog and man and as 2 h only in rabbit. This apparent elimination half-life is governed by the disposition of acidic metabolites of NA 872. In man and rabbit radioactivity is excreted almost completely into the urine, whereas in rat and dog biliary excretion is also observed. Routes of biotransformation are similar in all 4 species. NA 872 is metabolized by phase I reactions to NA 873 and finally to dibromoanthranilic acid. Phase II reactions with the parent compound and metabolites are observed mainly in man and rabbit.

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