The alkaloid L-(-)-scopolamine [L-(-)-hyoscine] competitively inhibits muscarinic receptors for acetylcholine and acts as a nonselective muscarinic antagonist, producing both peripheral antimuscarinic properties and central sedative, antiemetic, and amnestic effects. The parasympatholytic scopolamine, structurally very similar to atropine (racemate of hyoscyamine), is used in conditions requiring decreased parasympathetic activity, primarily for its effect on the eye, gastrointestinal tract, heart, and salivary and bronchial secretion glands, and in special circumstances for a CNS action. Therefore, scopolamine is most suitable for premedication before anesthesia and for antiemetic effects. This alkaloid is the most effective single agent to prevent motion sickness. Scopolamine was the first drug to be made commercially available in a transdermal therapeutic system (TTS-patch) delivering alkaloid. Recently, pharmacokinetic data on scopolamine in different biozlogic matrices were obtained most efficiently using liquid chromatographic-tandem mass spectrometric (LC-MS/MS) or gas chromatography online coupled to mass spectrometry. Pharmacokinetic parameters are dependent on the dosage form (oral dose, tablets; parenteral application; IV infusion; SC and IM injection). Scopolamine has a limited bioavailability if orally administered. The maximum drug concentration occurs approximately 0.5 hours after oral administration. Because only 2.6% of nonmetabolized L-(-)-scopolamine is excreted in urine, a first-pass metabolism is suggested to occur after oral administration of scopolamine. Because of its short half-life in plasma and dose-dependent adverse effects (in particular hallucinations and the less serious reactions, eg, vertigo, dry mouth, drowsiness), the clinical use of scopolamine administered orally or parenterally is limited. To minimize the relatively high incidence of side effects, the transdermal dosage form has been developed. The commercially available TTS-patch contains a 1.5-mg drug reservoir and a priming dose (140 microg) to reach the steady-state concentration of scopolamine quickly. The patch releases 0.5 mg alkaloid over a period of 3 days (releasing rate 5 microg/h). Following the transdermal application of scopolamine, the plasma concentrations of the drug indicate major interindividual variations. Peak plasma concentrations (Cmax) of approximately 100 pg/mL (range 11-240 pg/mL) of the alkaloid are reached after about 8 hours and achieve steady state. During a period of 72 hours the plaster releases scopolamine, so constantly high plasma levels (concentration range 56-245 pg/mL) are obtained, followed by a plateau of urinary scopolamine excretion. Although scopolamine has been used in clinical practice for many years, data concerning its metabolism and the renal excretion in man are limited. After incubation with beta-glucuronidase and sulfatase, the recovery of scopolamine in human urine increased from 3% to approximately 30% of the drug dose (intravenously administered). According to these result...

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The application of i.v. MMF is safe at a weight-adjusted dose between 25 and 34 mg/kg after allogeneic BSCT. The measured trough blood levels of MPA in patients after BSCT were ten times lower than in healthy volunteers. The toxicity induced by the conditioning therapy seems to negatively influence the pharmacokinetic behavior of MMF, MPA and MPAG.

An efficient method to lower the optical detection limit is described using the displacement of an absorption and emission band of an analyte after a polarity change in different solvents. This solvatochromic effect was used in a RP-HPLC assay for the fluorescence detection of mycophenolic acid (6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acid, MPA) and the prodrug mycophenolate mofetil (MMF), the N-(2-hydroxyethyl)morpholino ester of MPA. The rational to use fluorescence detection is based on the behavior of MMF and MPA, which fluoresce in a basic medium (pH >9.5). Following a simple protein precipitation, the analytes were separated in an isocratic RP-HPLC system. The postcolumn generation of the phenolate anions of MPA and MMF was achieved by addition of an aqueous sodium hydroxide solution regulated by a newly developed continuous-flow liquid control system. MPAG, not directly accessible for fluorescence detection, was analyzed after enzymatic deglucuronidation to MPA. Compared to published quantification limits for MPA and MMF by UV detection, this method is more than 100-fold more sensitive, with a lower limit of quantification of 45 fmol for both MPA and MMF.

Summary. This study was undertaken to evaluate the toxicity and pharmacokinetics of a dimethyl sulphoxide (DMSO)-based intravenous formulation of busulphan in the conditioning of 45 patients undergoing allogeneic or autologous stem cell transplantation (SCT). Busulphan was given as a single daily dose. In 15 patients a single dose of intravenous busulphan, given over 3 h in 1 d, was combined with additional oral (single daily) doses. Thirty patients received all four daily doses intravenously. Busulphan plasma levels were analysed using high performance liquid chromatography. There was no major acute toxicity with daily intravenous doses of 2´8±3´1 mg/kg infused over 3 h. No veno-occlusive disease (VOD) was seen in 30 patients receiving busulphan as an intravenous formulation over 4 d. In the group of 15 patients receiving three oral doses and one intravenous single daily dose, one patient experienced mild VOD. Pharmacokinetic samples were taken over at least 2 d of treatment in 44 patients. The area under the concentration time curve (AUC) values normalized for a dose of 1 mg/kg were 7000 ng/ml  h on d 1 and 5890 ng/ml  h on d 4, thus showing a moderate decrease over time. This was accompanied by a moderate increase of the clearance from 2´6 to 3´0 ml/min/kg. Administration of busulphan as a DMSO-based intravenous formulation was well tolerated. The total dose of busulphan can be given in four (rather than the typical 16) doses. With such a regimen, the intravenous administration becomes feasible on an outpatient basis.Keywords: intravenous busulphan, HSCT, pharmacokinetics.Oral busulphan (BU) was introduced into conditioning regimes for bone marrow transplantation in the early 1980s. Several aspects of BU pharmacokinetics have been correlated with outcome. The area under the concentration time curve (AUC) has been correlated with the frequency of hepatic complications, especially veno-occlusive disease (VOD), by some investigators (Grochow et al, 1989), although not all subsequent reports confirmed these associations (Schuler et al, 1994). Other groups found exposure to high BU levels to be associated with permanent hair loss or overall poor outcome (Ljungman et al, 1995;Ringden et al, 1999). Conversely, low levels were found to be associated with an increased incidence of graft rejection or relapse (Slattery et al, 1995(Slattery et al, , 1997), but again not in all studies (Baker et al, 2000). These observations suggest that individualization of therapy may be necessary, a goal which in our experience may be difficult to achieve with oral dosing because of the poor predictive value of one oral AUC for AUC after later doses. In order to reduce both intra-and interindividual variability of BU pharmacokinetics, an intravenous BU formulation using a dimethyl sulphoxide (DMSO) base was developed and initially evaluated in a canine model (Ehninger et al, 1995;Deeg et al, 1999). In human patients, using a BU/DMSO preparation as intravenous standard, we determined the bioavailability of oral BU to be 70% (Schuler e...

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We have previously described pharmacokinetic studies with a dimethylsulfoxide-based intravenous busulfan preparation in a canine model and in preliminary clinical trials. Using the same intravenous busulfan preparation, we carried out a dose escalation study to determine a marrow-ablative dose and to test the ability of autologous marrow to reconstitute hematopoiesis in dogs so treated. Busulfan was given intravenously at doses of 3.75 to 40 mg/kg. Marrow ablation was achieved at 20 mg/kg given either as a single dose or in four daily increments of 5 mg/kg each. There was a relative sparing of lymphocytes. A busulfan dose of 40 mg/kg resulted in severe central nervous system toxicity. Otherwise, nonhematopoietic toxicity was minimal and restricted to mild hepatic abnormalities. Four dogs were given busulfan at 20 mg/kg followed 30 hours later by infusion of autologous marrow, and all showed prompt and complete hematopoietic reconstitution. The area under the curve (AUC) determined by busulfan concentration in plasma over time was dose dependent, ranging from 12 to 100 microg x h/mL for busulfan doses of 3.75-20 mg/kg. There was a suggestion that the plasma half-life increased at the highest busulfan doses used. Intravenous administration of busulfan circumvented differences in bioavailability; nevertheless, considerable variations in the pharmacokinetic parameters were observed between individual animals. Thus, intravenous busulfan can be given safely and is effective in ablating hematopoiesis. However, factors other than absorption influence the AUC, and individualization of dosing may be required even with intravenous administration of the drug.

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