Pharmacokinetics of oral cyclosporin A when co-administered to enhance the oral absorption of paclitaxel

Mm, Malingré; Ww, ten Bokkel Huinink; Duchin, Kenneth L.; Jh, Schellens

doi:10.1097/00001813-200108000-00005

Cited by 12 publications

(5 citation statements)

References 9 publications

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“…Previous investigators have shown that it is possible to improve bioavailability of orally administered drugs through pharmacologic inhibition of drug metabolizing enzymes and transporters, [21][22][23][24] and to reduce interindividual variability of orally administered 5-fluroruracil through inhibition of the main enzyme of metabolism, dihydropyrimidine dehydrogenase using eniluracil. 25 Such strategies enhance clinical utility of drugs.…”

Section: Discussionmentioning

confidence: 99%

Ketoconazole Renders Poor CYP3A Phenotype Status With Midazolam as Probe Drug

Tham

Lee²,

Wang³

et al. 2006

Therapeutic Drug Monitoring

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Drugs metabolized by cytochrome CYP3A isoenzymes have wide interindividual variability and normally distributed plasma clearance distributions. This makes precise dosing difficult to achieve clinically, which may compromise safe therapy. We hypothesized that with potent inhibition of CYP3A, we could clinically render patients "poor metabolizer" phenotype status, and thus reduce interindividual pharmacokinetic variability of midazolam, a well-known CYP3A substrate. Intravenous bolus midazolam at doses of 2.5 mg and 1 mg were administered to 28 and 29 patients with cancer with and without co-administration of 200 mg of oral ketoconazole twice per day respectively for 3 days, starting 1 day before midazolam. Pharmacokinetic analyses of midazolam on both groups were derived using noncompartmental methods and compared. The mean clearance (CL) of midazolam was reduced 6 times by ketoconazole. Midazolam CL were normally distributed in both groups, and ranged from 1.7 to 51.9 and 1.4 to 8.2 L/hour in the control and ketoconazole groups, respectively, corresponding to a 7-fold reduction in dispersion between the 2 groups. Area-under-the-curve variability was reduced by >100%. A limited sampling model consisting of time points at 15 and 300 minutes was validated as a phenotype for CYP3A activity to facilitate the use of midazolam as a probe drug for CYP3A activity. Potent inhibition of CYP3A by ketoconazole reduced midazolam CL and area-under-the-curve variability, allowing for more precise achievement of therapeutic target drug exposure. Prospective evaluation of this approach, together with dose adjustment based on limited sampling, seems warranted.

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Section: Discussionmentioning

confidence: 99%

Ketoconazole Renders Poor CYP3A Phenotype Status With Midazolam as Probe Drug

Tham

Lee²,

Wang³

et al. 2006

Therapeutic Drug Monitoring

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“…In contrast, the A893S, A893T, and S1141T variants and the N21D/1236CϾT/A893S/3435CϾT haplotype are less sensitive to cyclosporin A inhibition of BODIPY-FL-paclitaxel transport. The coadministration of paclitaxel and cyclosporin A for the treatment of various cancers is currently under consideration (Malingré et al, 2001;Kuppens et al, 2005), and the current data may improve the design and interpretation of such studies. Based on studies showing that 1) P-gp substrates bind different domains (Loo and Clarke, 2002;Loo et al, 2003Loo et al, , 2006a and 2) cyclosporin A is a competitive inhibitor that alters P-gp conformation while in the drug-binding pocket (Loo and Clarke, 1997;Loo et al, 2003;Ejendal and Hrycyna, 2005;Suzuyama et al, 2007), there may be a synergistic effect with these variants in how they influence drug binding in the presence of cyclosporin A.…”

Section: Substrate-dependent Activity Of P-gp Variants 439mentioning

confidence: 99%

Substrate-Dependent Effects of Human ABCB1 Coding Polymorphisms

Gow¹,

Hodges²,

Chinn³

et al. 2008

J Pharmacol Exp Ther

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One of the many obstacles to effective drug treatment is the efflux transporter P-glycoprotein (P-gp), which can restrict the plasma and intracellular concentrations of numerous xenobiotics. Variable drug response to P-gp substrates suggests that genetic differences in ABCB1 may affect P-gp transport. The current study examined how ABCB1 variants alter the P-gpmediated transport of probe substrates in vitro. Nonsynonymous ABCB1 variants and haplotypes with an allele frequency Ն2% were transiently expressed in HEK293T cells, and the transport of calcein acetoxymethyl ester and 4,4-difluoro-4-bora3a,4a-diaza-s-indacene (BODIPY-FL)-paclitaxel was measured in the absence or presence of the P-gp inhibitor cyclosporin A. The A893S, A893T, and V1251I variants and the N21D/ 1236CϾT/A893S/3435CϾT haplotype altered intracellular accumulation compared with reference P-gp in a substratedependent manner. It is interesting that certain variants showed altered sensitivity to cyclosporin A inhibition that was also substrate-specific. These functional data demonstrate that nonsynonymous polymorphisms in ABCB1 may selectively alter P-gp transport and drug-drug interactions in a substrateand inhibitor-dependent manner.

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“…The bioavailability of cyclosporine may also be influenced by cremophor EL. It was shown that the AUC of cyclosporine decreased with increasing paclitaxel dose, which could be explained by micellar entrapment of cyclosporine in the gastrointestinal tract by cremophor EL 28 …”

Section: Oral Paclitaxelmentioning

confidence: 99%

Intravenous-to-Oral Switch in Anticancer Chemotherapy: A Focus on Docetaxel and Paclitaxel

Koolen

Beijnen

Schellens

2009

Clin Pharmacol Ther

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Oral administration of the taxanes docetaxel and paclitaxel is hampered by their affinity for drug transporters, especially ABCB1 (P-glycoprotein, Pgp); extensive first-pass metabolism by cytochrome P450 3A (CYP3A); and poor drug solubility. Preclinical studies in Pgp-deficient and wild-type mice demonstrated that modulation of either Pgp or CYP3A resulted in high systemic exposure to docetaxel or paclitaxel. This concept could successfully be translated to clinical trials.

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Pharmacokinetics of oral cyclosporin A when co-administered to enhance the oral absorption of paclitaxel

Cited by 12 publications

References 9 publications

Ketoconazole Renders Poor CYP3A Phenotype Status With Midazolam as Probe Drug

Ketoconazole Renders Poor CYP3A Phenotype Status With Midazolam as Probe Drug

Substrate-Dependent Effects of Human ABCB1 Coding Polymorphisms

Intravenous-to-Oral Switch in Anticancer Chemotherapy: A Focus on Docetaxel and Paclitaxel

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