Pharmacokinetic interference of doxorubicin with tolbutamide due to reduced metabolic clearance with increased serum unbound fraction in rats.

The study examined the effect of doxorubicin (DOX) on the hepatic expression of CYP2C and its activity for metabolizing tolbutamide (TB), a specific CYP2C substrate, in rats and whether the pharmacokinetics of tolbutamide were altered by doxorubicin exposure. The expression level of hepatic CYP2C11 was depressed 1 day after doxorubicin administration (day 1), and this effect on CYP2C11 was augmented on day 4. However, the expression level of hepatic CYP2C6 remained unchanged. The activity of tolbutamide 4-hydroxylation in hepatic microsomes was decreased with time following doxorubicin administration. Regarding the enzyme kinetic parameters for tolbutamide 4-hydroxylation on day 4, the maximum velocity (Vmax ) was significantly lower in the DOX group than that in the control group, while the Michaelis constant (Km ) was unaffected. On pharmacokinetic examination, the total clearance (CLtot ) of tolbutamide on day 4 was increased, despite the decreased metabolic capacity. On the other hand, the serum unbound fraction (fu ) of tolbutamide was elevated with a reduced serum albumin concentration in the DOX group. Contrary to CLtot , CLtot /fu , a parameter approximated to the hepatic intrinsic clearance of unbound tolbutamide, was estimated to be significantly reduced in the DOX group. These findings indicate that the metabolic capacity of CYP2C11 in the liver is depressed time-dependently by down-regulation after doxorubicin exposure in rats, and that the decreased enzyme activity of TB 4-hydroxylation in hepatic microsomes reflects the pharmacokinetic change of unbound tolbutamide, not total tolbutamide, in serum.

Melanin-producing medullary thyroid carcinoma with transformation to melanoma: A case report.

Only one case of melanoma arising from melanin-producing medullary thyroid carcinoma (MTC) has been reported previously. In the present study, a second such case was reported and compared with the previous one. The patient was an 86-year-old male who presented with a right anterior neck mass. Ultrasound revealed a nodule measuring 49x48x40 mm in the right lobe of the thyroid. The levels of serum calcitonin (2,298 pg/ml) and carcinoembryonic antigen (CEA; 27.0 ng/ml) were markedly elevated. Aspiration cytology revealed suspected malignant anaplastic thyroid carcinoma and total thyroidectomy without neck nodal dissection was performed. On gross observation, the nodule was well encapsulated, soft, solid and black. Light microscopy indicated that the nodule was composed mainly of large, occasionally huge, pleomorphic cells with a solid or alveolar growth pattern. On immunohistochemistry, these cells were positive for melan-A and S-100 protein, and negative for thyroid transcription factor 1, calcitonin, chromogranin A and CEA. In the subcapsular area, melanin-producing MTC was intimately intermingled with the pleomorphic cells. No primary site of the melanoma was detectable in other organs. At three years after surgery, the patient died due to metastasis of the melanoma to the brain. The previously reported case had no detectable recurrence or distant metastasis up to 11 years after surgery. In comparison with that case, the present case had a similar morphology but the outcome was poorer. Thus, the prognosis of melanoma that transforms from MTC appears to remain uncertain.