Liquid chromatographic quantitation of the lactone and the total of lactone and carboxylate forms of 9-nitrocamptothecin in human plasma

Derakhshandeh, Katayoun; Dadashzadeh, Simin

doi:10.1016/j.jchromb.2004.12.025

Cited by 4 publications

(4 citation statements)

References 21 publications

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“…The terminal half-life is estimated to be 10 -15 h, which is similar to that reported for oral 9-AC (9.72 h) [4]. A major issue in trying to evaluate the effect of dose on pharmacokinetics, toxicity and activity is that there is significant interpatient and intrapatient variability in the handling of rubitecan and its major active metabolite, 9-AC [10,15,[17][18][19][20][21]. Thus, it is possible that adjusting doses in individual patients utilising pharmacokinetic sampling might be of benefit to optimise antitumour activity while minimising toxicity, although this has not been tested in trials.…”

Section: Pharmacokinetics and Metabolismsupporting

confidence: 56%

“…It is composed of a planer aromatic five-ring system with a lactone group. The lactone moiety is required for optimal inhibition of topoisomerase I and thus antitumour activity of the molecule [1,4,10]. Similar to all of the currently clinically available camptothecins, this lactone group is converted to the carboxylate form in basic or neutral conditions.…”

Section: Chemistrymentioning

confidence: 99%

“…Sensitive and specific methods for measuring rubitecan have been developed [10,[17][18][19][20]; however, despite these, it has been difficult to carefully evaluate the amount of drug that remains in the 9-NC lactone form in plasma as well as the levels of specific metabolites. This is partly because many of the studies were carried out prior to this methodology being available but also because of the difficulties of ensuring the careful processing of plasma samples to prevent the conversion to the Expert Opin.…”

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

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Rubitecan

Clark¹

2005

Expert Opinion on Investigational Drugs

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The only approved camptothecins for use in patients to date (topotecan and irinotecan) are delivered intravenously. Thus, an oral camptothecin analogue that would provide the convenience of oral delivery with the flexibility for a variety of prolonged treatment schedules would be advantageous. Rubitecan is an orally available camptothecin analogue that also has potential for delivery transdermally or by inhalation. Like all of the camptothecins, its antitumour activity is mediated through the inhibition of DNA topoisomerase I, which is involved in relaxing supercoiled DNA, which is important for the process of DNA replication and RNA transcription. Rubitecan exists in equilibrium as 9-nitro-camptothecin (9-NC) and 9-amino-camptothecin (9-AC), a metabolite that is thought to be active although it failed in clinical trials. Both 9-NC and 9-AC contain a lactone ring that is required for optimal activity with the carboxylic acid (open ring) forms being significantly less active or inactive. A more acidic environment favours the lactone ring structure, whereas neutral or basic conditions favour the conversion to the carboxylic acid form. In addition to issues of lactone ring stability at physiological pH (true for all of the camptothecin analogues), there is pharmacokinetic variability that has had to be dealt with during the development of rubitecan. Preclinically, rubitecan has shown activity against a broad spectrum of tumour types in in vitro and in vivo human tumour xenograft models. Frustratingly, the level of activity of an agent in preclinical models has not always translated into similar activity against human tumours in clinical trials. To date, with the exception of pancreatic and possibly ovarian cancer, rubitecan has had disappointing activity against a number of other solid tumours in relatively small Phase I/II trials; however, it has shown sufficient activity against pancreatic cancer, a malignancy that remains difficult to treat, to continue to be evaluated in clinical trials for this indication. Results of clinical trials in the next few years should determine whether rubitecan can find a role in cancer therapy.

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Section: Pharmacokinetics and Metabolismsupporting

confidence: 56%

Section: Chemistrymentioning

confidence: 99%

Section: Pharmacokinetics and Metabolismmentioning

confidence: 99%

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Rubitecan

Clark¹

2005

Expert Opinion on Investigational Drugs

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“…The accuracy was determined by comparing the calculated concentrations from standard curves to theoretical concentrations. Finally, the limits for accuracy values were set in the range of 85%-115% (15,16).…”

Section: Validation Of Analytical Methodsmentioning

confidence: 99%

Therapeutic Drug Monitoring of Vancomycin: The Relationship Between Trough Plasma Concentration and Creatinine Clearance

Salahshoor

Kurd

Taher

et al. 2020

Avicenna J Pharm Res

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Background: In this study which was conducted in Besat hospital (Hamadan, Iran), the therapeutic drug monitoring (TDM) of vancomycin (VAN) was carried out based on the quantification of VAN trough in intensive care unit (ICU) patients. Methods: The study population was selected from ICU patients treated by intravenous VAN. To determine VAN trough, blood samples were taken from patients before the fourth dose. Then, trough concentrations were determined by newly developed high-performance liquid chromatography (HPLC) and compared with the conventional method of immunoassay. Twenty patients were included based on the aim of the study. Results: The mean value of the trough for the studied patients was 26.31±18.05 μg/mL. For 16 (80%) patients, trough levels were found to be less than 10 μg/mL. For 12 (60%) patients, creatinine clearance was less than 90 mL/min and more than 120 mL/min. The mean value of creatinine clearance for the studied patients was 95.49± 25.74 mL/min. Based on the results, there was a significant relationship between VAN trough concentration and creatinine clearance (P=0.045). Conclusion: In general, the HPLC method is more sensitive than immunoassay for the determination of VAN in plasma samples. However, VAN dosing based on creatinine clearance is not enough for achieving the goal trough level but measuring the creatinine clearance and trough concentration are considered as vital aspects for the TDM of VAN.

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