Tomoo Funaki

Enterohepatic Circulation Model for Population Pharmacokinetic Analysis

An enterohepatic circulation model based on physiological aspects of biliary excretion has been developed for population pharmacokinetic analysis. Mycophenolate mofetil was selected as a model drug for validation of the model. As a secondary objective, the model was used for pharmacokinetic comparison among different races.

The disposition of the tolcapone 3-O-methylated metabolite is affected by the route of administration in rats.

Abstract— Catechol‐O‐methyltransferase (COMT) catalyses the transfer of the methyl group from S‐adenyl‐l‐methionine (SAM) to one of the hydroxy groups of a catechol, usually the hydroxy group in position 3. COMT is present mainly in a soluble form (S‐COMT) in the cytosol, but a small fraction is bound to cell membranes (MB‐COMT). MB‐COMT has higher affinity for the catechol substrate than does S‐COMT by a factor of > 10, and high MB‐COMT activity is observed in the intestinal muscle layer. The present study investigates the effect of the administration route on the disposition of the tolcapone 3‐O‐methylated metabolite following intravenous and oral tolcapone administration in rats. Tolcapone is a substrate for COMT although the 3‐O‐methylated metabolite produced has no pharmacological actions. The 3‐O‐methylated metabolite was eliminated very slowly following oral administration of tolcapone, and its concentration approached a plateau level, which was in contrast to the situation following intravenous administration of tolcapone. It is thought that the oral dose of tolcapone receives a high exposure to MB‐COMT in the intestinal muscle layer during its absorption, and tolcapone seems to form a complex with MB‐COMT having a high affinity constant (i.e. a very low Ki). The fraction of the intravenous dose of tolcapone metabolized to the 3‐O‐methylated metabolite at 10 mg kg−1 was 2·6%, whereas those of the oral doses, which were corrected by the bioavailability, were 5·4% for 20 mg kg−1 and 2·7% for 40 mg kg−1.

Estimation of kinetic parameters in the inactivation of an enzyme by a suicide substrate

A method was developed to estimate the extended Michaelis constant and maximum velocity of a suicide substrate from the time-course of remaining enzyme activity with the use of simulation data calculated from the representative kinetic model for a suicide substrate proposed by Walsh et al. (Walsh, C., Cromartie, T., Marcotte, P. and Spencer, R. (1978) Methods Enzymol. 53, 437-448). For this purpose an analytical equation for the time-course of remaining enzyme activity, based on the suicide kinetic model, was derived by the steady-state method reported by Tatsunami et al. (Tatsunami, S., Yago, N. and Hosoe, M. (1981) Biochim. Biophys. Acta 662, 226-235). The accuracy of this analytical solution was proved by comparing the result with the exact solution obtained by numerical computation. A method was also developed to estimate the most important factor for a suicide substrate, the partition ratio, from the time-course of remaining enzyme activity.

Clinical pharmacokinetics of 2'-deoxy-2'-methylidenecytidine (DMDC), a deoxycytidine analogue antineoplastic agent

This article reviews the Clinical Pharmacokinetics of a deoxycytidine analogue of cytarabine, 2′-deoxy-2′-methylidenecytidine (DMDC). DMDC belongs to the antimetabolite class of anticancer drugs and is phosphorylated into its active, triphosphate, form within the tumour cell. Cancer cell death appears to be a result of the impairment of DNA synthesis by the triphosphate form. DMDC undergoes deamination to the inactive 2′-deoxy-2′-methylideneuridine (DMDU), its main plasma metabolite.Following intravenous administration at 30 to 450 mg/m2, DMDC has low systemic clearance (10 to 15 L/h/m2), moderate volume of distribution (nominally similar to total body water) and a short elimination half-life of between 2 and 6 hours. Renal clearance of DMDC accounts for approximately 30 to 50% of total clearance.Following oral administration of DMDC at 12 to 50 mg/m2, mean maximum DMDC plasma concentrations are within the 100 to 400 μg/L range and are generally reached within 2 hours. Oral bioavailability of DMDC is in the order of 40%, largely as a result of first-pass metabolism in the gut and liver. This first-pass effect results in considerable interpatient variability in systemic exposure to DMDC after oral administration. The systemic availability of DMDC is proportional to the administered dose and, although there was evidence that systemic exposure to DMDC decreased on repeated administration, there are no excessive time-dependent changes in systemic exposure to DMDC.Following oral administration, DMDC is metabolised in the gut wall and liver by deamination to DMDU. The kidneys eliminate DMDC and DMDU, with up to 50% of the administered dose recovered in urine, on average, as parent drug and metabolite.Dose escalation to the maximum tolerated dose was facilitated by a pharmacokinetically guided dose escalation strategy. DMDC has shown activity in non-small-cell lung cancer and colorectal cancers following oral administration. Several tumour responses are observed at the highest doses of DMDC, indicating a possible dose-response relationship with this drug. The main clinical adverse event of DMDC therapy is myelotoxicity.The haematological toxicity of DMDC was schedule dependent; twice daily administration was associated with greater toxic effects than a once daily regimen. A pharmacokinetic-pharmacodynamic model characterised the relationship between plasma DMDC concentrations and the time-dissociated toxicity. This model-dependent approach may be used to predict the consequences of as-yet-untested therapy as well as relating acceptable risks of haematological toxicity to target drug exposure.

Lack of an Effect of Madopar on the Disposition of Tolcapone and its 3‐O‐Methylated Metabolite in Rats

The effect of Madopar (benserazide and l‐dopa, 1:4) on the disposition of the new selective inhibitor of catechol‐O‐methyltransferase, tolcapone, in rats was investigated. There was no statistically significant difference in the pharmacokinetic parameters of tolcapone in the presence or absence of Madopar except for a change in the mean residence time after oral administration. Thus, we rejected the hypothesis that the consumption of S‐adenyl‐l‐methionine by Madopar would change the disposition of tolcapone.

The behavior of remaining enzyme activity in a suicidal enzyme system

We derived an equation which describes the plot of the remaining enzyme activity versus ratio of initial concentration of suicide substrate to that of enzyme to obtain a partition ratio from the time-course of remaining enzyme activity. The simulation data calculated from the representative kinetic model for a suicide substrate were used to verify this equation, which approximated steady state kinetics. Although the time-dependent loss of enzyme activity is usually characterized by pseudo-first-order kinetics, the present results show that pseudo-first-order kinetics are followed only when the ratio of initial concentration of suicide substrate to that of enzyme is greater than the partition ratio. Our results also show that the present method can be used to obtain the partition ratio of a suicide substrate from the time-course of the remaining enzyme activity when the suicide substrate is given an arbitrary concentration of one, where the ratio of initial concentration of suicide substrate to that of enzyme is less than the partition ratio. The theoretically verified equation was also checked against reported experimental data for a microsomal enzyme system.