Different absorption behaviors among steroid hormones due to possible interaction with P-glycoprotein in the rat small intestine.

The intestinal absorption of ten steroid hormones was evaluated in the rat small intestine, especially focusing on the interaction with intestinal P-glycoprotein (P-gp). Hydrocortisone, prednisolone, 6alpha-methylprednisolone, and dexamethasone (adrenocortical steroid hormones) all disappeared in a regional-dependent manner (duodenum>jejunum>ileum). The decreased rate of disappearance in the lower small intestine seemed to be due to the involvement of absorption barriers like P-gp. In contrast, all sex hormones including progesterone exhibited very high absorbability in the entire small intestine (duodenum=jejunum=ileum), possibly demonstrating the absence of restricted absorption by intestinal P-gp. Progesterone enhanced the rate of disappearance of vinblastine but did not affect 6alpha-methylprednisolone. In the presence of vinblastine and verapamil, on the other hand, the rate of disappearance of 6alpha-methylprednisolone increased significantly. It was demonstrated that there was a plural P-gp family, which had different substrate specificities, in the rat intestine and that steroid hormones interacted with them as substrates or inhibitors in a very complex manner.

Involvement of intestinal P-glycoprotein in the restricted absorption of methylprednisolone from rat small intestine.

The interaction between steroid hormones and intestinal P-glycoprotein was investigated by measuring intestinal absorption from rat small intestine in situ. Prednisolone and hydrocortisone were rapidly absorbed from the entire small intestine. In contrast, methylprednisolone absorption was significantly retarded in jejunum and ileum by an intestinal efflux system. In the presence of verapamil an quinidine, the retarded absorption of methylprednisolone was completely recovered, suggesting that P-glycoprotein is responsible for the unique features of methylprednisolone absorption. A requisite for the substrate of intestinal P-glycoprotein seemed to be 6 alpha-methyl group in the steroid structure. Substrate specificity of intestinal P-glycoprotein to steroid hormones was shown to be in part different from those in other tissues such as adrenal gland. Little of all three steroid hormones disappeared in the supernatant of mucosal homogenate from rat small intestine, indicating that intestinal metabolism of these steroid hormones was relatively small.

[A study of first and second line chemotherapies in gestational choriocarcinoma].

Twenty-eight patients with choriocarcinoma have received the three kinds of combination chemotherapy since 1983 at our department, i.e., MOA consisting of moderate dose methotrexate (MTX), actinomycin-D (Act-D) and vincristine, MEA (moderate dose MTX, Act-D and etoposide) and FA (high dose 5-Fluorouracil and Act-D). The clinical and laboratory data obtained in the 28 patients were summarized as follows; 1. The MOA regimen was administered to 4 patients primarily and to 2 secondarily. All of the 6 patients attained remission, but finally two (33.3%) developed relapse. 2. The MEA regimen was administered to 12 patients primarily and to 12 secondarily. Of the 24 patients, five (20.8%) were found to be resistant to the MEA regimen. Nineteen patients (79.2%) attained remission, but 2 (10.5%) developed recurrence. 3. The FA regimen was attempted in one patient primarily and in 6 secondarily. Although one patient died, the remaining 6 achieved remission and one relapse has been observed in the 6 cases. 4. By applying the above mentioned 3 combination chemotherapy regimens, the overall survival rate was pushed up from 64% to 90% in choriocarcinoma patients. 5. Three patients finally died of the disease but not from the side effects of the combination chemotherapies. The major adverse effects were alopecia, nausea, vomiting and myelosuppression. In particular, serious myelosuppression was caused by the MEA or FA regimen in 5-7% of all chemotherapy courses.

[The effect of etoposide on ovarian function in patients with gestational trophoblastic disease].

Thirty-four patients with low risk gestational trophoblastic disease were treated with etoposide alone. Within 60 days after treatment, synthetic luteinizing hormone releasing hormone (LH-RH: 100 micrograms) was injected intravenously. The serum concentrations of LH, follicle-stimulating hormone (FSH) before and 30, 60, 120 minutes after LH-RH administration, estradiol (E2) and progesterone were measured. In addition, the basal body temperature (BBT) was taken continuously to evaluate ovulation. (1) The patients aged 40 or more in whom serum LH and FSH levels were higher before LH-RH administration, showed excessive response to LH-RH. These excessive responses were 45.5% and 7.1% in patients in their thirties and twenties, respectively. (2) Serum E2 and progesterone levels decreased with advanced age, which was not affected by total doses of etoposide. (3) Seven (77.8%) patients over 40 years were found to have anovulatory cycles, based on their BBT, and ovulation was confirmed in all the patients under 40 years. (4) Eleven pregnancies were confirmed. Nine delivered apparently healthy infants. The influence of etoposide on ovarian function was transient except for patients over 40 years old.

[A clinicopathological study on gestational trophoblastic disease comparing with high risk criteria and diagnostic score of choriocarcinoma].

In the past 15 years, 274 patients with the gestational trophoblastic disease have been treated at Chiba University and the diagnosis of 125 patients was confirmed pathologically. There were 55 cases (44%) in the high risk and 70 cases (56%) in the low risk group with the following criteria: (1) the urinary hCG titer was more than 100,000 IU/L; (2) the duration between antecedent pregnancy and the start of treatment was more than 1 year; (3) antecedent pregnancies were full-term or abnormal pregnancies except hydatidiform mole. These pathologically confirmed patients were evaluated with the choriocarcinoma diagnostic score. From this study, the following results were obtained: (1) The overall remission rates in high risk and low risk patients were 79.1%, 100%, respectively. (2) Out of 55 patients with high risk diagnosed pathologically, 49 (89.1%) patients had choriocarcinomas. On the other hand, 65 (92.9%) patients with low risk had invasive moles. (3) The discrepancies between the pathological and the clinical diagnosis chiefly depended on the inadequate evaluation of recurrent cases and the pretreatment urinary hCG. (4) Compared with our criteria, the choriocarcinoma diagnostic scoring system more closely corresponds to the pathological diagnosis but this system is more complex and inadequate than our criteria for older up patients that have not been adequately followed up.