Acute cholangitis induced by carbamazepine.

We report a case of a patient with fever and intrahepatic cholestasis induced by carbamazepine (CBZ). This adverse reaction has been described in only a single case. We observed complete resolution of the hepatic damage once the agent was discontinued. CBZ rechallenge was followed by recurrence of all symptoms and abnormalities. Hepatic function improved again when CBZ was discontinued.

Influence of intravenous infusion duration on the tissue drug concentration profile.

The influence of intravenous infusion duration of a single dose of drug on the time course of drug concentration in the peripheral compartment of the classical two-compartment pharmacokinetic model was studied by computer simulation. The aim was to illustrate the general relationships among infusion duration T, dose, minimum effective concentration MEC at the effector (tissue) site, maximum tissue drug concentration C2,max, and the duration of effective tissue concentrations tD,tiss for those drugs where there is an equilibration delay between concentration at the effector site and plasma. Simulations of C2,max vs. T for meperidine, sulfamethoxazole, ampicillin, and metronidazole showed that, although maximum plasma concentration may decrease markedly with increasing T, C2,max decreased only slightly with increasing T. Simulations of the influence of T on the duration of effective plasma concentrations tD and tD,tiss of metronidazole showed that for a given T, tD,tiss may be greater than or less than tD, depending on the dose, and that it is possible to obtain effective concentrations in the tissue compartment even though the infusion duration is too long to achieve effective concentrations in plasma. It was found that, depending on the dose, it was possible to cause an increase in tD,tiss compared with bolus administration by increasing the infusion duration of the dose. It was also found that increasing T could cause opposite changes in tD and tD,tiss (compared with bolus administration, respectively), e.g., an increase in tD and a decrease in tD,tiss or vice versa, depending on the dose. It should thus be possible to make precise predictions of the influence of T on drug concentration at the effector site for individual drugs by incorporating effect compartment modeling into the analysis.

Relationships among duration of infusion, dose, dosing interval, and steady-state plasma concentrations during intermittent intravenous infusions: studies with metronidazole.

Relationships among duration of infusion (T), dose, dosing interval (tau), maximum and minimum plasma drug concentrations at steady state (Cmax,ss and Cmin,ss, respectively), and the duration of effective plasma concentrations (tD) during multidose intermittent infusion regimens were studied by computer simulation using metronidazole as a model drug. Pharmacokinetic parameter values for metronidazole were obtained from the literature and the minimum effective plasma concentration (MEC) was taken as 6.0 micrograms/ml. Increasing the infusion period of the dose reduces Cmax,ss, but increases Cmin,ss. If intermittent bolus injection of a given dose of drug results in effective plasma concentrations for the entire dosage interval (i.e., Cmin,ss,bolus greater than MEC), then infusion of that dose over any period (T less than or equal to tau) will also result in effective concentrations for the entire dosage interval. However, if the dosage is such that Cmin,ss,bolus less than MEC, the relationships among duration of infusion, dose, dosage interval, and duration of effective plasma concentrations are complex. Therefore a nomogram was developed to allow selection of dose, dosing interval, and infusion period such that Cmax,ss and Cmin,ss could be maintained within a desired range.

Kinetics of D-alpha-tocopherol in a water soluble base in man.

The kinetics of D-alpha-tocopherol (vitamin E) were investigated in 10 healthy, adult volunteers following a single dose of 500 iu D-alpha-tocopherol. Plasma concentration/time curves fitted using a one compartment open model, showed a rise to 12 +/- 1.9 mumol litre-1 above endogenous values over 8-9 h and then a tailing away to 7 +/- 1.1 mumol litre-1 after 24 h.

Effect of formulation on the bioavailability of retinol, D-alpha-tocopherol and riboflavine.

Formulation factors influencing vitamin bioavailability have been investigated, with vitamins A, E and B2, formulated in a new liquid vehicle (Aqua-Biosorb) and encapsulated into soft gelatin capsules, being compared with commercial formulations. There was an enhanced vitamin bioavailability from the new vehicle which appeared to be related to the surfactant system employed and the absence of vegetable oil in the formulation.