Order Elimination Kinetics Research Articles

New and Simple Method to Predict Dosage of Drugs Obeying Simple Michaelis-Menten Elimination Kinetics and to Distinguish Such Kinetics from Simple First Order and from Parallel Michaelis-Menten and First Order Kinetics

It has been found empirically that either average or minimum steady-state plasma concentrations (Css) of drugs obeying Michaelis-Menten elimination kinetics give essentially linear plots on semilogarithmic graph paper when Css is plotted versus the maintenance dose (D) or dose rate (R). The equations of such straight lines may be converted to the following nonlinear equation: Css = abD which fits the Css,D data essentially as well as D = VmCss/(Km + Css). The parameter b is analogous to unity plus the interest fraction in logarithmic growth or compound interest calculations, and each drug appears to have a characteristic value of this parameter, with extremely small intersubject variation. From the above equation the following equation, Dn+1 = Dn + 1n(Cn+1/Cn)1n b can be derived, which forms the basis of predicting the needed dosage, Dn+1, to obtain a desired steady-state concentration, Cn+1, using one initial steady-state concentration, Cn, obtained with dose, Dn, and using a population value of b for the drug. It appears that it is the value of the "initial capital" (i.e., a in relation to the initial dose) rather than the "interest fraction" (i.e., b - 1) that causes most of the intersubject variation in Css of a given drug. Several drugs illustrate the usefulness of the method. A semilogarithmic plot also appears to be an excellent method to distinguish simple Michaelis-Menten kinetics from parallel Michaelis-Menten and first order elimination kinetics and from simple first order kinetics with steady-state data in the range 0.3-3 Km.

Two compartment kinetic model with multiple artificial capillary units.

A two compartment in-vitro model was designed to simulate human pharmacokinetics and to expose bacterial cultures to changing drug concentrations, thereby avoiding limitations of conventional antibiotic testing at constant drug levels. Serially placed bacterial compartments, representing extravascular infection sites, interface with a central compartment through artificial capillaries. Drug concentrations within the culture chambers closely mimic interstitial concentrations in vivo. Simultaneous first order elimination kinetics of two drugs with different half-lives were simulated to study antibacterial effects of drug combinations. This in-vitro model is an efficient tool for optimal dosage regimen design and the study of synergistic/antagonistic effects of antibiotic combinations.

In-vitro model for simultaneous simulation of the serum kinetics of two drugs with different half-lives.

Simultaneous administration of two drugs is frequently practised in clinical chemotherapy because of the synergistic potential of drug combinations. During in-vitro testing of the effect of such drug combinations, differences in the pharmacokinetic properties of the two drugs should be considered. This paper presents the mathematical background and the technical components of an in-vitro model that allows the simultaneous simulation of first order elimination kinetics of two drugs with different half-lives. The model allows simulations of multiple dose regimens of either bolus injections or continuous infusions of each drug.

Elimination of oral cimetidine in chronic renal failure and during haemodialysis.

1 The absorption and elimination of a single oral dose of 400 mg cimetidine was studied in fourteen fasting patients with impaired renal function. In addition, the dialysance of cimetidine was studied in five patients on haemodialysis. 2 The absorption was somewhat, but clinically insignificantly delayed. A second unexplained peak in the absorption curve was found. 3 First order elimination kinetics were confirmed and the length of time of a cimetidine concentration over 0.5 mg/l could be correlated with creatinine clearance. 4 The magnitude of extra renal elimination was estimated to be approximately one fourth of total cimetidine elimination in normal patients and seemed unaffected by impaired renal function. 5 A dose schedule based on AUC found in the patients in renal failure is suggested. The recommendations for daily oral dose range from 300 mg (at borderline dialysis) to 1000 mg in mild renal failure. The suggested doses will give an average plasma concentration of the same order as seen in patients with normal renal function.

Pharmacokinetics of bromocriptine during continuous oral treatment of Parkinson's disease.

The plasma kinetics of bromocriptine (BCT), a long-acting dopamine agonist, was studied in twelve patients with Parkinson's disease, using a newly developed gas chromatographic method of analysis. Each patient received BCT for at least three weeks in a constant but different dose regimen. Concomitant treatment with 1-DOPA was not allowed. During a 6-day hospitalization period, a blood sample was taken immediately before the afternoon dose at 14.00 h (Cmin) to determine the steady-state level. On the 6th day blood samples were collected every hour during two 8 h dose intervals. The results showed a significant correlation between the mean values of the AUC and the Cmin. First order elimination kinetics appeared to be followed by BCT, at least for the plasma concentrations commonly found. Considerable inter-individual variation was demonstrated both for the dose/plasma concentration ratio and for calculated plasma clearances. No serious side-effects were observed during the investigation.

Pharmacokinetics and side-effects of clonazepam and its 7-amino-metabolite in man.

Clonazepam (CNP) and its principal metabolite in plasma, 7-amino-CNP (ACNP), have been investigated in a prospective study of 27 newly diagnosed epileptics and correlated with specified side-effects. At a daily dose of 6 mg, the average plasma levels of both substances were about 50ng/ml, and individual values ranged from 30 to about 80 ng/ml. There was a linear correlation between changes in dose and the resulting plasma levels, which indicates first order elimination kinetics. Side-effects were frequent, but neither their severity nor their occurrence could be related to plasma levels or to the rate of increase in plasma concentration of the drug. Three out of five patients who developed serious dysphoria had significantly high CNP levels. The concentration of ACNP was considerably increased in four patients who subsequently suffered from withdrawal symptoms. Drug interaction with diphenylhydantoin, i.e. decreased CNP level, was observed in all five patients who received both compounds. In general it is not yet possible to define an upper limit for the plasma levels of CNP and ACNP at which toxicity occurs. In patients treated with conventional doses of CNP, measurement of plasma concentration is not required, except in special circumstances, because of the lack of correlation between plasma level and side-effects.

A Review with a Case History on the Effect of Renal Failure

Although the majority of individuals medicated with diphenylhydantoin require doses in the range of 4–6 mg/kg/day (300–400 mg/day), there are many people who are known to deviate from this average in their requirements. Other persons may be stablized on a given dose of diphenylhydantoin, yet develop toxic signs or demonstrate lack of therapeutic effect at a later time. This paper reviews basic pharmacokinetics and elimination data for diphenylhydantoin, as well as the various parameters recognized as influencing diphenylhydantoin dosing requirements. A case history is presented1 to illustrate the possible effects of renal failure and how one individual's requirements changed as his clinical status changed. Among the physiological factors considered are liver function, renal function, genetic influences on metabolic disposition, and alterations that occur in serum protein binding of diphenylhydantoin. Physical characteristics that are considered include variability in formulation of various solid oral dosage forms, hazards of oral suspensions of diphenylhydantoin, efficacy of intramuscular injections, and failure of diphenylhydantoin to obey first order elimination kinetics. Finally, interaction of other drug products with diphenylhydantoin is discussed and summarized.

Elimination kinetics of amobarbital in mothers and their newborn infants.

Plasma concentrations of amobarbital were measured in mothers with mild hypertension at term and their newbom infants after administration of a single dose of sodium amobarbital before delivery. Similar drug concentrations were found in cord and matemal plasma immediately after delivery. From the declining amobarbital concentration values, first order elimination kinetics were demonstrated in all cases. The plasma half‐life of amobarbital was 2.5 fimes as long in the newborn as in the mothers. The plasma concentration of the drug's major metabolite, hydroxyamobarbital, increased during 12 to 24 hours after delivery in 2 of the mothers and children and decreased thereafter.

Clinical use of a bio-assay of serum digitoxin activity.

In 73 patients on digitoxin maintenance medication a progressive increase of mean serum digitoxin activity was found with increasing dose. However, there were considerable variations within each group. Change of dose was followed by a new steady state level close to that predicted by zero order absorption-first order elimination kinetics of the drug. In atrial fibrillation the expected fall in ventricular rate was always observed with increasing serum concentration. No significant difference in serum level was found 24 h after identical peroral and intravenous doses had been given to different groups of patients. However, significantly higher serum values were found in normal subjects than in patients with heart disease after identical peroral treatment. This probably indicates poorer absorption by the patients. In 13 subjects, the estimated serum digitoxin half-lives were 3.7 to 11.3 days. These large differences may explain much of the variation in serum values found during steady state therapy. The elimination curves were in accordance with a first order drug kinetics. Only three patients with definite digitalis intoxication were seen, all of whom had high serum values which did not overlap patients without features of intoxication. The results showed that several patients on maintenance therapy were under-digitalized. It is hoped that this or similar methods may make it possible to adjust individual treatment to compensate for differences in absorption, distribution and elimination, and thereby to increase the benefits and decrease the risks of toxicity of digitoxin therapy.