uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
A mechanism-based pharmacokinetic-enzyme model for cyclophosphamide autoinduction in breast cancer patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Show others and affiliations
1999 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 48, no 5, 669-677 p.Article in journal (Refereed) Published
Abstract [en]

Aims This study investigated the pharmacokinetics of cyclophosphamide (CP) and its main metabolite 4-hydroxycyclophosphamide (4-OH-CP) in patients with breast cancer undergoing high dose chemotherapy prior to autologous stem cell transplantation. An enzyme turn-over model was also developed to study the time course of cyclophosphamide induction. Methods Fourteen patients received a combination of CP (6 g m(-2)), thiotepum (500 mg m(-2)) and carboplatin (800 mg m(-2)) as a 96 h infusion. Plasma concentrations of CP and 4-OH-CP were determined with h.p.l.c. and a pharmacokinetic and enzyme turn-over model applied to data using NONMEM. Results CP plasma concentrations were described by a two-compartment model with a noninducible and an inducible pathway, the latter forming 4-OH-CP. In the final enzyme model, CP affects the amount of enzymes by increasing the enzyme production rate. CP concentrations decreased during the infusion with no subsequent change in 4-OH-CP concentrations. CP inducible and noninducible clearance were estimated to 1.76 1 h(-1) (90% C.I. 0.92-2.58) and 1.14 1 h(-1) (0.31-1.85), respectively. The induction resulted in an approximately doubled CP clearance through the inducible pathway at the end of treatment. The model predicted the enzyme turn-over half-life to be 24 h. Conclusions The presented mechanism-based enzyme induction model where the pharmacokinetics of the inducer and the enzyme pool counterbalance each other successfully described CP autoinduction. It is reasonable to believe that CP affects its own elimination by increasing the enzyme production rate and thereby increasing the amount of enzyme by which CP is eliminated.

Place, publisher, year, edition, pages
1999. Vol. 48, no 5, 669-677 p.
Keyword [en]
4-hydroxycyclophosphamide, autoinduction, breast cancer, cyclophosphamide, enzyme induction model, pharmacokinetics
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-208924ISI: 000083676600005OAI: oai:DiVA.org:uu-208924DiVA: diva2:655497
Available from: 2013-10-11 Created: 2013-10-11 Last updated: 2013-10-11Bibliographically approved

Open Access in DiVA

No full text

Search in DiVA

By author/editor
Svensson, Ulrika S H
By organisation
Department of Pharmacy
In the same journal
British Journal of Clinical Pharmacology
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Total: 116 hits
ReferencesLink to record
Permanent link

Direct link