Serial assessment of pulmonary lesion volume by computed tomography allows survival prediction in invasive pulmonary aspergillosis.

BACKGROUND: Serial chest CT is the standard of care to establish treatment success in invasive pulmonary aspergillosis (IPA). Data are lacking how response should be defined. METHODS: Digital CT images from a clinical trial on treatment of IPA were re-evaluated and compared with available biomarkers. Total volume of pneumonia was added up after manual measurement of each lesion, followed by statistical analysis. RESULTS: One-hundred and ninety CT scans and 309 follow-up datasets from 40 patients were available for analysis. Thirty-one were neutropenic. Baseline galactomannan (OR 4.06, 95%CI: 1.08-15.31) and lesion volume (OR 3.14, 95%CI: 0.73-13.52) were predictive of death. Lesion volume at d7 and trend between d7 and d14 were strong predictors of death (OR 20.01, 95%CI: 1.42-282.00 and OR 15.97, 95%CI: 1.62-157.32) and treatment being rated as unsuccessful (OR 4.75, 95%CI: 0.94-24.05 and OR 40.69, 95%CI: 2.55-649.03), which was confirmed by a Cox proportional hazards model using time-dependent covariates. CONCLUSION: Any increase in CT lesion volume between day 7 and day 14 was a sensitive marker of a lethal outcome (>50%), supporting a CT rescan each one and 2 weeks after initial detection of IPA. The predictive value exceeded all other biomarkers. Further CT follow-up after response at day 14 was of low additional value. KEY POINTS: • CT evaluation offers good prediction of outcome for invasive pulmonary aspergillosis. • Predictive capability exceeds galactomannan, blood counts, and lesion count. • Any progression between day 7 and day 14 constitutes a high-risk scenario.

Phase II dose escalation study of caspofungin for invasive Aspergillosis.

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.

Monitoring paracetamol metabolism after single and repeated administration in pediatric patients with neoplastic diseases.

INTRODUCTION: Paracetamol (PCM) is frequently used in pediatric patients with neoplastic disease. It is metabolized mainly by conjugation, but at therapeutic concentrations, a small fraction of the drug undergoes oxidative metabolism via cytochrome P450 forming the hepatotoxic intermediate N-acetyl-p-benzo-quinone-imine (NAPQI) which is usually conjugated with glutathione and excreted as paracetamol mercapturate and paracetamol cysteine. OBJECTIVE: The aim of this monitoring study was to evaluate PCM metabolism with minimal intervention during routine treatment with single and repeated administration in patients undergoing antineoplastic therapy. METHOD: A total of 107 urine samples collected 4-12 h after PCM administration from 29 children undergoing antineoplastic treatment, and 10 children without antineoplastic treatment were analyzed for PCM, PCM glucuronide (PCM-G), PCM sulfate (PCM-S), PCM mercapturate (PCM-M) and PCM cysteine (PCM-C). RESULTS: The median (range) percentages for metabolites in urine were: a) in children with and without chemotherapy after the first administration: PCM: 0 (0-100) and 4 (0-11)%, PCM-G: 55 (0-88) and 51 (18 - 68)%, PCM-S: 30 (0-73) and 32 (22-57)%, PCM-(M+C): 13 (0-52) and 9 (0-24)%, respectively; b) after repeated administration in children with chemotherapy: PCM: 0 (0-51)%, PCM-G: 42 (7-100)%, PCM-S: 28 (0-70)%, PCM-(M+C): 24 (0-66)%. CONCLUSION: The pattern of PCM excretion in children undergoing antineoplastic treatment regimens is highly variable. Repeated administration is associated with a significant increase in the products of oxidative metabolism. This might indicate an increase in metabolism via the hepatotoxic NAPQI.

Frequent but borderline methylation of p16 (INK4a) and TIMP3 in medulloblastoma and sPNET revealed by quantitative analyses.

Certain risk groups among tumors of the central nervous system (CNS) in children take an almost inevitably fatal course. The elucidation of molecular mechanisms offers hope for improved therapy. Aberrant methylation is common in malignant brain tumors of childhood and may have implications for stratification and therapy. Methylation of p16 (INK4A), p14 (ARF), TIMP3, CDH1, p15 (INK4B )and DAPK1 in medulloblastoma (MB) and ependymoma has been discussed controversially in the literature. DUTT1 and SOCS1 have not previously been analyzed. We examined methylation in MB, sPNET and ependymoma using methylation-specific PCR (MSP), quantitative Combined Bisulfite Restriction Analysis (COBRA) and direct and clone sequencing of bisulfite PCR products. We detected methylation of p16 (INK4A) (17/43), p14 (ARF) (11/42) and TIMP3 (9/44) in MB and others by MSP. CDH1 was not only methylated in MB (31/41), but also in normal controls. Evaluation of MSP results by quantitative COBRA and sequencing yielded methylation between the detection limits of COBRA (1%) and MSP (0.1%). Only p16 (INK4A )and TIMP3 were methylated consistently in medulloblastomas (p16 (INK4A ) 14%, TIMP3 11%) and p16 (INK4A) also in anaplastic ependymomas (1/4 tumors). Methylation ranged from 1-5%. Evaluation of methylation using MSP has thus to be supplemented by quantitative methods. Our analyses raise the issue of the functional significance of low level methylation, which may disturb the delicate growth factor equilibrium within the cell. Therapeutic and diagnostic implications urge into depth analyses of methylation as a mechanism, which might fill some of the gaps of our understanding of brain tumor origin.

Serum asparaginase activities and asparagine concentrations in the cerebrospinal fluid after a single infusion of 2,500 IU/m(2) PEG asparaginase in children with ALL treated according to protocol COALL-06-97.

BACKGROUND AND PROCEDURE: Pharmacological surrogate parameters are considered a useful tool in estimating the treatment intensity of asparaginase (ASNase) preparations. When a pegylated ASNase (single infusion of 2,500 IU/m(2) polyethylene glycol (PEG)-ASNase, Oncaspar) was introduced into the treatment protocols of the German Cooperative Acute Lymphoblastic Leukaemia (COALL) study group, this was accompanied by a drug monitoring programme measuring serum ASNase activity and asparagine (ASN) concentrations in the cerebrospinal fluid (CSF) in 70 children. RESULTS: Four hundred fifty-nine serum samples from 67 evaluable patients showed medians of ASNase activity of 1,189.5, 824.5, 310.5, 41 and 4 U/l on day 7 +/- 1, 14 +/- 1, 21 +/- 1, 28 +/- 1 and 35 +/- 1 respectively. One hundred eighty-four samples from 59 patients were evaluable for ASN concentrations in the CSF. The medians of ASN concentration were <0.2, 0.2, 0.9 and 3.2 microM on day 14 +/- 1, 21 +/- 1, 28 +/- 1 and 35 +/- 1 respectively. When relating CSF ASN levels to the serum ASNase activity measured on the same day, a median of 1.2 microM CSF ASN was associated with values of serum ASNase activity between > or =2.5 and <100 U/l. Serum ASNase activity values > or =100 U/l were associated with a median CSF ASN of <0.2 microM, with 13/27 samples being incompletely depleted. CONCLUSIONS: The treatment intensity achieved with PEG ASNase in the present study appears to be acceptable based on the surrogate of serum ASNase activity. However, the pharmacological objective of ASNase treatment, that is, complete CSF ASN depletion with an ASNase activity >100 U/l, was not ensured. Nevertheless, one must also be aware that the minimum ASN concentration required for leukaemic cell growth is yet to be established.

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters.

BACKGROUND: To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children. PROCEDURE: Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors. RESULTS: Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity. CONCLUSIONS: While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.

Drug monitoring of PEG-asparaginase treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma.

This is an updated review of the pharmacokinetic profile of PEG-asparaginase (PEG-ASNase) in childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL). In a total of 271 children undergoing ALL/NHL or relapsed ALL treatment according to the Berlin-Frankfurt-Münster (BFM) protocols, drug monitoring of ASNase serum activity was performed after PEG-ASNase infusions. From December 1996 to July 2000, 1667 samples after 362 intravenous administrations of either 500, 750, 1000 or 2500 IU/m2 PEG-ASNase were analyzed. Three weeks after infusion when relating the ASNase activity to the four-dose levels significant differences were not observed. Large interpatient variability was seen at each dose level resulting in a relevant number of patients not achieving adequate treatment intensity. Neither the extent of ASNase pre-treatment nor a prior event of a hypersensitivity reaction against unmodified ASNase had any impact on PEG-ASNase pharmacokinetics. It is concluded that escalation of the dose of PEG-ASNase did not result in a significant prolongation of time with activity values considered therapeutic. Depending on the desired endpoint, a second administration of PEG-ASNase seems to be more favorable than increasing the dose. For a safer recommendation, further investigations assessing the pharmacodynamic profile are required. Drug monitoring is advisable for early detection of patients with rapid elimination in order to ensure maximum treatment intensity.

Drug monitoring of low-dose PEG-asparaginase (Oncaspar) in children with relapsed acute lymphoblastic leukaemia.

Use of asparaginase (ASNase) in the treatment of relapsed childhood acute lymphoblastic leukaemia (ALL) is associated with a high rate of hypersensitive reactions. 'Silent' inactivation may additionally reduce treatment intensity. Therefore, PEG-ASNase (Oncaspar), a polyethylene glycol conjugate of the native Escherichia coli-ASNase, was introduced into the Berlin-Frankfurt-Münster (BFM) 96 treatment protocol for relapsed ALL under drug monitoring conditions. A single i.v. dose of 500 IU/m2 PEG-ASNase, substituted for the native ASNases, was administered to supply a plasma activity of 100 IU/l for 1 week. From November 1997 to March 2000, 35 patients from 23 BFM-associated hospitals, with or without a previous allergic reaction to one or both native preparations, underwent monitoring. After 82 applications, a total of 270 samples were submitted to be tested for ASNase activity. The ASNase activity on the day of the administration and the following day ranged between < 20 and 693 IU/l, with a median of 413 IU/l (53 samples). The median on d 7 +/- 1 was 199 IU/l (range <20--421 IU/l; 41 samples) and on d 14 +/- 1, 105 IU/l (range <20--188 IU/l; 19 samples). An ASNase activity of > 100 IU/l was seen on d 7 in 36 activity time courses of 52 interpretable applications (69%). Intraindividual variability of activity time courses was low. However, a rapid decrease in ASNase activity after repeated applications was observed in 4 out of 20 children. Previously experienced allergic reactions to native ASNases did not influence PEG-ASNase pharmacokinetics. PEG-ASNase is a useful alternative to the native ASNases in children with relapsed ALL. Whenever possible, drug monitoring should be performed to identify patients with 'silent' inactivation.

Simulation tool for schedule-dependent etoposide exposure based on pharmacokinetic findings published in the literature.

It is the aim of this study to establish a simulation tool for etoposide (Eto) which can be used to interpret drug monitoring data in clinical practice and to design new schedules for future protocols. As schedule dependency was observed for Eto, knowledge of concentration-time profiles is important. Pharmacokinetic data from children after low-dose i.v. administration of Eto together with data reported in the literature were used to construct the simulation tool. Validation was performed by independently reproducing various published data. Dose linearity of AUC was shown over the whole dose range of 20-2000 mg/m2 reported in the literature and fits the predictions by the simulation tool. There was no difference in clearance between children and adults. Close agreement was found between predicted and reported concentration-time profiles after various administration schedules. However, subgroups with significantly altered pharmacokinetics of Eto, such as patients with renal impairment or concurrent cisplatin chemotherapy, were excluded from the comparisons. In these patients values predicted for a 'regular' patient might be used as a base for possible dose modifications. In summary, a pharmacokinetic model of high predictive value is presented which allows simulations of Eto concentration-time profiles for low- as well as high-dose conditions and various infusion times.

Asparagine synthetase activity in paediatric acute leukaemias: AML-M5 subtype shows lowest activity.

Lack of sufficient cellular activity of asparagine synthetase (AS) in blast cells compared with normal tissue is thought to be the basis of the antileukaemic effect of L-asparaginase in acute lymphoblastic leukaemia (ALL). Although L-asparaginase is routinely used in ALL, its role and value in the treatment of acute myelogenous leukaemia (AML) is still being discussed. To evaluate the pharmacological basis for L-asparaginase treatment, we established pretreatment monitoring of the intracellular AS activity in blast cells of patients with AML and ALL. There was no general difference in AS activity between ALL and AML samples. Significantly lower AS activity, however, was found in the B-lineage ALL subgroups as well as AML-M5.

Population pharmacokinetic approach to compare oral and i.v. administration of etoposide.

The antitumor effect of etoposide (ETO) may be related to duration of exposure to a relatively low serum level while myelosuppression may be dependent on peak ETO serum levels. With regard to such therapeutic ranges, duration of exposure to predefined plasma ETO concentration ranges and the related AUC (expressed as percent of total AUC, pAUC) were used to compare pharmacokinetic profiles after oral and short time i.v. (1 h infusion) administration of identical ETO doses (100 mg/m2). Patients included in this study received i.v. (18 patients, short-term infusions) or oral (16 patients) ETO on different treatment schedules. Plasma ETO concentrations were determined by HPLC and population pharmacokinetic parameters were calculated (P-Pharm 1.4). Despite an 'apparent bioavailability' of 59%, oral administration of ETO was associated with the same time of exposure to a predefined 'therapeutic range' of 0.5-3 mg/l and a significantly higher pAUC compared to i.v. administration. By contrast, time of exposure to the probably more myelotoxic concentration range above 3 mg/l was significantly shorter and the related pAUC was highly significantly lower after oral than after i.v. administration. These findings demonstrate that oral ETO therapy is at least equivalent to short time i.v. therapy in terms of achieving specific target concentration ranges and avoiding peak concentrations.

Inhibition of smoking-induced platelet aggregation by aspirin and pycnogenol.

The effects of a bioflavonoid mixture, Pycnogenol, were assessed on platelet function in humans. Cigarette smoking increased heart rate and blood pressure. These increases were not influenced by oral consumption of Pycnogenol or Aspirin just before smoking. However, increased platelet reactivity yielding aggregation 2 hours after smoking was prevented by 500 mg Aspirin or 100 mg Pycnogenol in 22 German heavy smokers. In a group of 16 American smokers, blood pressure increased after smoking. It was unchanged after intake of 500 mg Aspirin or 125 mg Pycnogenol. In another group of 19 American smokers, increased platelet aggregation was more significantly reduced by 200 than either 150 mg or 100 mg Pycnogenol supplementation. This study showed that a single, high dose, 200 mg Pycnogenol, remained effective for over 6 days against smoking-induced platelet aggregation. Smoking increased platelet aggregation that was prevented after administration of 500 mg Aspirin and 125 mg Pycnogenol. Thus, smoking-induced enhanced platelet aggregation was inhibited by 500 mg Aspirin as well as by a lower range of 100-125 mg Pycnogenol. Aspirin significantly (p<0.001) increased bleeding time from 167 to 236 seconds while Pycnogenol did not. These observations suggest an advantageous risk-benefit ratio for Pycnogenol.

[Pharmacokinetic aspects of oral administration of etoposide]. / Pharmakokinetische Aspekte der oralen Applikation von Etoposid.

BACKGROUND: Etoposide is a cytotoxic agent which is frequently employed in paediatric oncology and which is available for intravenous as well as oral application. Many advantages of the formulation for oral use have been opposed by concerns about its interindividually varying bioavailability. The influence of the dosage of etoposide on its activity and toxicity ("schedule dependency") has also been discussed. The present paper deals with the pharmacokinetics of oral etoposide focusing on the interindividual variability. PATIENTS: Sixteen patients aged between 3 and 73 years received oral etoposide at a dosage of 28 mg/m2 to 149 mg/m2 in combination with oral trofosfamide for palliation. METHOD: HPLC was used to measure total and free serum etoposide in 16 patients, and the etoposide concentration in several urine samples from 8 patients. Pharmacokinetic parameters were normalized to a dosage of 100 mg/m2. RESULTS: The peak serum concentration, the time to peak concentration, the area under the concentration-time curve, the terminal half-life and the apparent clearance after oral application were calculated to be 6.7 micrograms/ml, 2.1 h, 51.8 (microgram.h/ml)/(100 mg/m2), 5.6 h, and 40.3 ml/min for total etoposide, and 0.23 microgram/ml, 1.9 h, 1.76 (microgram.h/ml)/ (100 mg/m2), 5.9 h, and 1172 ml/min for free serum etoposide, respectively. On an average, urinary recovery of etoposide was 21% of the oral dose. The fraction of free etoposide was calculated to be close to 4%. Regarding the systemic exposure to etoposide, a variation coefficient of 40% was determined. Additional studies showed that the interindividual variability mainly concerned the peak levels, while the duration for which intermediate etoposide levels were maintained varied less between individuals. On simulating different dosage schedules, it was seen that the duration of intermediate concentrations (0.5-2 micrograms/ml) may be extended significantly by dividing the daily dose of etoposide into two oral applications. CONCLUSION: The total systemic exposure under oral etoposide treatment varies considerably between individuals. Extended intervals of intermediate etoposide concentration and less variation are, however, possible with oral therapy. Dividing the daily dose into two applications seems advisable. Future studies are warranted to test hypotheses on pharmacokinetic-pharmacodynamic aspects by pharmacological drug monitoring.

Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia.

The enzyme asparaginase is an important element in the therapy of acute lymphoblastic leukaemia (ALL). The usual asparaginase dose as prescribed in the ALL-BFM-86/90 treatment protocol for the therapy of ALL is 10,000 IU/m2 at 3 d intervals and had been developed on the basis of the E. coli asparaginase preparation Crasnitin from the Bayer company. Using the described schedule the E. coli asparaginase preparation from the Medac company shows significantly higher biological activity than the Bayer preparation. These findings prompted an attempt to reduce the dose of the Asparaginase medac under careful pharmacokinetic and pharmacodynamic monitoring. At the first step of dose reduction in ALL treatment protocol I, 11 children received 5000 IU/m2 of Asparaginase medac. Another 15 children were given 2500 IU/m2 of the enzyme at the second step of dose reduction. Prior to each asparaginase dose, blood samples were taken to determine amino acids and trough enzyme activity. Concurrent with the asparaginase monitoring, the coagulation parameters were measured. 96% of samples from the first step of dose reduction (5000 IU/m2 every third day) showed complete L-asparagine depletion (< 0.1 microM), the median trough enzyme activity was 265 IU/l. At the second step of dose reduction (2500 IU/m2) complete L-asparagine depletion was seen in 97% of samples, and the median trough enzyme activity was 102 IU/l. Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Asparaginase medac dose reduced from the usual 10000 IU/m2 down to 5000 IU/ m2 or 2500 IU/m2, applied at 3 d intervals, was sufficient to achieve complete L-asparagine depletion in serum. Changes of the fibrinogen levels was significantly less pronounced in the group on 2500 IU.

Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations.

The antileukaemic enzyme L-asparaginase is used to achieve the greatest possible reduction in blood levels of the amino acid asparagine, an essential factor for the growth of leukaemic blasts. There are two main sources of the enzyme, E. coli and Erwinia. Faced with increasing reports of treatment complications, we established a programme to monitor enzyme activity and asparagine levels in serum, in children receiving treatment for acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL). Trough asparagine and asparaginase levels were measured in 49 children on induction treatment with different E. coli preparations (Asparaginase medac, Crasnitin) and in 52 children on re-induction (Asparaginase medac, Crasnitin, and, in the event of allergic reactions, Erwinase) just prior to each sequential application of 10000 U/m2 of asparaginase. Measurements were made by an enzyme assay and an HPLC method. During induction, both Escherichia coli preparations induced the desired reduction in asparagine, but the asparaginase activity with Asparaginase medac was significantly higher than with Crasnitin (median of trough levels 475 versus 74 U/l). Under re-induction treatment (median, Asparaginase medac 528 U/l, Crasnitin 49 U/l, and Erwinase < 20 U/l) complete asparagine depletion was recorded on day 3 in more than 90% of Asparaginase medac samples, more than 60% of Crasnitin samples and in 26% of Erwinase samples. The latter two groups included some children with unchanged asparagine levels and no measurable enzyme activity. Different asparaginase preparations are not readily interchangeable. When Asparaginase medac is used instead of Crasnitin, and identical dose will be associated with significantly higher enzyme activity, well above the level required for complete asparagine depletion. Clinical studies will need to specify both the preparation and the dose to be used. When substitution of an alternative drug is mandatory owing to allergic reactions, monitoring is advisable.

Activation of beclomethasone dipropionate by hydrolysis to beclomethasone-17-monopropionate.

The relative affinity of beclomethasone (B), beclomethasone-17-monopropionate (17-BMP), beclomethasone-21-monopropionate (21-BMP), and beclomethasone dipropionate (BDP) has been determined. BDP binds to the glucocorticoid receptor with about half the affinity of the potent glucocorticoid dexamethasone (Dexa), B was found to be 0.75 times less active than Dexa. The 21-BMP has no binding affinity whereas the 17-BMP is about 13 times as potent as Dexa. The affinity data indicate that metabolism of BDP to 17-BMP is an important activation step. To evaluate the relationship between local and systemic activity incubation studies with BDP in human lung, simulated gastric and intestinal fluid and plasma were performed. In cytosol from human lung cells BDP is hydrolysed rapidly to the more stable 17-BMP. During gastric passage BDP is stable but is immediately hydrolysed to 17-BMP in intestinal fluid. In human plasma BDP is hydrolysed to 17-BMP and an interesterification of 17-BMP to the inactive 21-BMP was also found.