Enzyme and Transporter Kinetics for CPT-11 (Irinotecan) and SN-38: An Insight on Tumor Tissue Compartment Pharmacokinetics Using PBPK.

BACKGROUND: Computational tools are becoming more and more powerful and comprehensive as compared to past decades in facilitating pharmaceutical, pharmacological and clinical practice. Anticancer agents are used either as monotherapy or in combination therapy to treat malignant conditions of the body. A single antineoplastic agent may be used in different types of malignancies at different doses according to the stage of the disease. OBJECTIVE: To study the behavior of CPT-11 (Irinotecan) and its metabolite SN-38 in tumor tissue compartment through the Whole Body-Physiologically Pharmacokinetics (WB-PBPK) and to determine the activity of metabolic enzymes and transporters participating in the disposition of CPT-11 and SN-38 working in their physiological environment inside the human body. METHODS: Whole body PBPK approach is used to determine the activity of different metabolic enzymes and transporters involved in the disposition of CPT-11 and its active metabolite, SN-38. The concentrations and pharmacokinetic parameters of the parent compound and its metabolite administered at clinically applicable dose via the intravenous route in the tumor tissue are predicted using this approach. RESULTS: The activity rate constants of metabolic enzymes and transporters of CPT-11 are derived at their natural anatomic locations. Concentration-time curves of CPT-11 and SN-38 with their 5th to 95th percentage range are achieved at the tumor tissue level. Mean tumor tissue pharmacokinetics of both compounds are determined in a population of 100 individuals. CONCLUSION: Tumor tissue concentration-time curves of CPT-11 and SN-38 can be determined via PBPK modeling. Rate constants of enzymes and transporters can be shown for healthy and tumor bearing individuals. The results will throw light on the effective concentration of active compound at its target tissue at the clinically applied IV dose.

Anticoagulant, antiplatelet and antianemic effects of Punica granatum (pomegranate) juice in rabbits.

Pomegranate (Punica granatum L., Punicaceae) is a good source of minerals and phytochemicals with diverse pharmacological activities such as anxiolytic, antidepressant, hypoglycemic, hypolipidemic, and anti-inflammatory activities. Effects of P. granatum on blood parameters and coagulation have, however, been little studied. The aim of the study was to assess the outcome of P. granatum on coagulation and anticoagulation factors at different doses on blood samples of healthy white rabbits. Blood samples of the animals were collected twice during the study and biochemical assays were performed to assess the effect on hematological, coagulation, anticoagulation, and platelet aggregation. Significant changes were observed in erythrocytes, hemoglobin, and mean corpuscular hemoglobin concentration, while bleeding and thrombin time were also prolonged significantly. There was significant increase in protein C, thrombin antithrombin complex levels, and decrease in platelet aggregation and fibrinogen concentration, in a dose-dependent manner. The results of hematological and coagulation assays lead to the speculation about a possible antianemic and cardioprotective effect of P. granatum.

Evaluation of hypoglycemic and hypolipidemic activity of methanol extract of Brassica oleracea.

AIM: The hypoglycemic and hypolipidemic effects of the methanol extract of Brassica oleracea var. capitata (MEB) was evaluated in alloxan-induced diabetic rabbits. METHOD: The study was conducted on twenty-eight healthy white rabbits of either sex. All animals were equally divided into four groups. After confirmation of hyperglycemia, the animals of the treated and standard groups were administered MEB (500 mg·kg(-1)) and glibenclamide (10 mg·kg(-1)), respectively for 15 and 30 days. The animals of the normal and diabetic controls received normal saline 1 mL/day equivalent to the volume of doses given to the test and standard animals. Biochemical tests were performed at the end of dosing, i.e. the 16(th) and 31(st) days. RESULTS: The MEB revealed a decrease of 106.6 mg·dL(-1) in fasting blood glucose as compared to diabetic control, which was almost comparable to glibenclamide; both of these changes were highly significant. The decrease in total cholesterol and low density lipoprotein was 94.3 and 96.5 mg·dL(-1), respectively, whereas the high-density lipoprotein was increased by 26.7 mg·dL(-1), as compared to diabetic control. All of the changes in lipid profile were statistically significant. CONCLUSION: These results suggest the potential of MEB as a hypoglycemic and hypolipidemic agent.

Analgesic, anti-inflammatory and anti-platelet activities of the methanolic extract of Acacia modesta leaves.

The current study was aimed to evaluate Acacia modesta for analgesic, anti-inflammatory, and anti-platelet activities. The analgesic and anti-inflammatory effects were assessed in rodents using acetic acid and formalin-induced nociception, hot plate and carrageenan-induced rat paw oedema tests. The intraperitoneal (i.p.) administration of the methanolic extract (50 and 100 mg/kg) produced significant inhibition (P\0.01) of the acetic acid-induced writhing in mice and suppressed formalin-induced licking response of animals in both phases of the test. In the hot plate assay the plant extract (100 mg/kg) increased pain threshold of mice. Naloxone (5 mg/kg i.p.) partially reversed the analgesic effect of the extract in formalin and hot plate tests.A. modesta (100 and 200 mg/kg i.p.) exhibited sedative effect in barbiturate-induced hypnosis test similar to that produced by diazepam (10 mg/kg i.p.). The plant extract(50-200 mg/kg i.p.) produced marked anti-inflammatory effect in carrageenan-induced rat paw oedema assay comparable to diclofenac and produced a dose-dependent(0.5-2.5 mg/mL) inhibitory effect against arachidonic acid induced platelet aggregation. These data suggest that A. modesta possesses peripheral analgesic and antiinflammatory properties, with analgesic effects partially associated with the opioid system.

Presence of blood-pressure lowering and spasmolytic constituents in Buddleja crispa.

This aim of this study was to investigate the crude extract of Buddleja crispa (Bc.Cr) and its active constituent(s) for their antihypertensive and antispasmodic activities. The Bc.Cr caused a dose-dependent (3-10 mg/kg) fall in mean arterial pressure in rats under anesthesia. In rabbit aorta preparations, Bc.Cr (0.03-1 mg/mL) caused inhibition of high K(+) (80 mM) precontractions. The Bc.Cr (0.03-1 mg/mL) also inhibited spontaneous and high K(+) precontractions in rabbit jejunum preparations, suggestive of calcium channel blocking (CCB) activity. CCB activity was further confirmed when pretreatment of the tissues with Bc.Cr (0.03-0.10 mg/mL) caused a rightward shift in Ca(++) concentration response curves, similar to verapamil. Among the pure compounds, BdI-H3 was more potent against the high K(+) than spontaneous contractions and was around eight times more potent than Bc.Cr against the spontaneous contractions while the other two compounds, BdI-2 and BH-3 were inactive. Activity-directed fractionation revealed that the hexane fraction was more potent against K(+) precontractions. These data indicate that Bc.Cr possesses a blood-pressure lowering effect, mediated possibly through CCB, though additional mechanism(s) cannot be ruled out. Among the pure compounds, Bdl-H3 is likely to be the active compound involved in the spasmolytic and possibly BP lowering effect of the parent crude extract.

Cholinomimetic and calcium channel blocking activities of Carthamus oxycantha.

The crude extract of Carthamus oxycantha (Co.Cr) and its fractions were studied in vitro for their possible spasmogenic and spasmolytic activities. Co.Cr (0.03-10 mg/mL) caused an atropine sensitive spasmogenic effect in guinea-pig ileum. In spontaneously contracting rabbit jejunum preparations, Co.Cr caused a dose-dependent (0.03-3.0 mg/mL) spasmogenic effect, followed by relaxation at the next higher doses of 5.0-10.0 mg/mL. In the presence of atropine, the spasmogenic effect was blocked and the relaxant effect was observed at lower doses (0.1-5.0 mg/mL), shifting the inhibitory dose-response curves to the left. Co.Cr also inhibited K(+) (80 mm)-induced contractions in atropinized preparations at similar doses, suggesting calcium channel blockade (CCB) activity. The CCB effect was further confirmed when pretreatment of the tissue with Co.Cr produced a dose-dependent shift in the Ca(++) dose-response curves to the right, similar to that caused by verapamil. Activity-directed fractionation revealed that the spasmolytic effect was concentrated in organic fractions in the following order of potency: hexane > ethylacetate > chloroform, while the aqueous fraction exhibited spasmogenic and weak spasmolytic effects. These results indicate that Carthamus oxycantha contains a combination of spasmogenic (cholinergic) and spasmolytic (calcium antagonist) constituents.