The distribution ofo,p′-DDD (Mitotane) among serum lipoproteins in normo- and hypertriglyceridemia

Gebhardt, D. O. E.; Moolenaar, A. J.; Seters, A. P. van; Velde, E. A. van der; Leuven, J.A. Gevers

doi:10.1007/bf00685956

Cited by 24 publications

(24 citation statements)

References 23 publications

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“…The estrogen-like activity of mitotane may be involved; however, the reported increases in HDL-c with estrogen therapy have been only 7–15% and we could not see a difference in HDL-c rise between men and women [20, 21]. It was also hypothesized that mitotane stimulates HDL-c synthesis by inducing the activity of the liver cytochrome P450 [23]. Scavenger receptor class B member 1 (SR-BI) is the primary receptor for the selective uptake of HDL-c and is located mainly in the liver and steroidogenic organs [24].…”

Section: Discussionmentioning

confidence: 99%

Mitotane-Induced Hyperlipidemia: A Retrospective Cohort Study

Shawa

Denız

Bazerbashi

et al. 2013

International Journal of Endocrinology

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Limited data are available about mitotane-nduced hyperlipidemia. We retrospectively analyzed lipid data in 38 patients with adrenocortical carcinoma (ACC) who received mitotane therapy with emphasis on HDL cholesterol (HDL-c) and clinical predictors of lipid changes. At baseline, the mean levels of HDL-c, LDL-c, and triglycerides were 53.3 mg/dL, 114.4 mg/dL, and 149 mg/dL, respectively. HDL-c, LDL-c, and triglyceride concentrations significantly increased with mitotane therapy to a mean HDL peak (HDL-P) of 86.3 mg/dL (P < 0.001), a mean LDL peak of 160.1 mg/dL (P < 0.001), and a mean triglyceride peak (Tg-P) of 216.7 mg/dL (P = 0.042). HDL-P positively correlated with mitotane concentration (r = 0.52, P < 0.001), while LDL-P levels and Tg-P did not. Gender, body mass index, cortisol overproduction, baseline levels of HDL-c, and triglyceride did not predict change in HDL-c. Similar changes were noticed in subgroup analysis after excluding patients who were using lipid-lowering agents. In conclusion, in ACC patients, mitotane caused significant increases in HDL-c that may counteract the deleterious atherosclerotic effects of LDL-c and Tg rise. Understanding the mechanism of HDL change may lead to the discovery of novel HDL-c-elevating drugs.

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Section: Discussionmentioning

confidence: 99%

Mitotane-Induced Hyperlipidemia: A Retrospective Cohort Study

Shawa

Denız

Bazerbashi

et al. 2013

International Journal of Endocrinology

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“…However, such mechanisms remain to be elucidated. For instance, mitotane is bound to lipoproteins in the plasma (30,31) and access to target tissue such as the brain is dependent on lipoprotein profiles (32). Furthermore, mitotane has been shown to affect lipoprotein profiles by increasing low-density lipoprotein and high-density lipoproteins (28).…”

Section: Discussionmentioning

confidence: 99%

High-dose mitotane strategy in adrenocortical carcinoma: prospective analysis of plasma mitotane measurement during the first 3 months of follow-up

MauclèreDenost

Leboulleux

Borget

et al. 2012

European Journal of Endocrinology

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Background: The benefit-to-risk ratio of a high-dose strategy at the initiation of mitotane treatment of adrenocortical carcinoma (ACC) remains unknown. Methods: To evaluate the performance of a high-dose strategy, defined as the highest tolerated dose administered within 2 weeks and maintenance therapy over 4 weeks, we conducted a single-center, prospective study with two main objectives: to evaluate the percentage of patients who achieve a plasma mitotane level above 14 mg/l and to evaluate the tolerance of mitotane within the first 3 months of treatment. Plasma mitotane levels were measured monthly using HPLC. Results: Twenty-two patients with ACC were prospectively enrolled. The high-dose mitotane strategy (4 g/day or more in all patients, with a median of 6 g/day within 2 weeks) enabled to reach the therapeutic threshold of O14 mg/l at 1, 2, or 3 months in 6/22 patients (27%), 7/22 patients (32%), and 7/22 patients (32%) respectively. In total, a therapeutic plasma mitotane level was reached in 14 out of 22 patients (63.6%) during the first 3 months in ten patients, and after 3 months in four patients. Grade 3-4 neurological or hematological toxicities were observed in three patients (13.6%). Conclusion: Employing a high-dose strategy at the time of mitotane initiation enabled therapeutic plasma levels of mitotane to be reached within 1 month in 27% of the total group of patients. If this strategy is adopted, we suggest that mitotane dose is readjusted according to plasma mitotane levels at 1 or/and 2 months and patient tolerance.

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“…29 Mitotane-induced LDL formation probably promotes its uptake in the adrenals; hypertriglyceridemia, by contrast, may counteract the entry of mitotane into the brain or adrenals, and thus work as a resistance mechanism. 29 The lipid disorders induced by mitotane administration may in turn provoke altered drug pharmacokinetics. In light of this, the concomitant administration of triglyceride-lowering drugs, such as gemfibrosil, would be advisable for improving mitotane activity.…”

Section: Discussionmentioning

confidence: 99%