John G. Wagner

Linear Pharmacokinetic Equations Allowing Direct Calculation of Many Needed Pharmacokinetic Parameters from the Coefficients and Exponents of Polyexponential Equations Which Have Been Fitted to the Data

It is shown that if the numerical values of the coefficients and exponents of the polyexponential equation describing the whole blood (plasma or serum) concentration after administration of a drug by bolus intravenous injection, or during or after termination of a constantrate intravenous infusion, are known, then many needed pharmacokinetic parameters may be obtained directly. Parameters readily calculated by simple arithmetic are as follows: plasma or serum clearance, Clp; volume of plasma compartment, Vp; volume of distribution at steady state, Vdss; V{darea} or Vβ, extrapolated volume of distribution, Vdexr; half-life of elimination, t1/2; amount metabolized and/or excreted to time t, (Ae); amount in the body at time t, Ab; amount in the plasma (reference) compartment at time t, Ap; and amount in other compartments at time t, Ao. Simulations have shown that the equations yield the correct answers for an n-compartment mammillary model with central compartment elimination only, when rate constants, dose, and a value of Vp have been assigned. Since whole blood (plasma or serum) concentrationtime data always lead to ambiguities as to which specific model is involved, the equations are most appropriate.

Pharmacokinetics of ethanol after oral administration in the fasting state

A nonlinear relationship between the total area under the blood ethanol concentration-time curve and the orally administered dose (mg/kg) of ethanol was observed in fasting subjects. A preliminary model, based on physiological considerations, was elaborated and shown, for the first time, to describe the entire time course of blood alcohol concentrations after four different doses of alcohol. The model could be refined by further experimentation.

Properties of the Michaelis-Menten equation and its integrated form which are useful in pharmacokinetics

Some old equations are reviewed and some new equations have been derived which indicate certain properties of the Michaelis-Menten equation and its integrated forms. Simulated data which obey Michaelis-Menten kinetics have been plotted in various ways to illustrate special relationships. An equation is derived which accurately estimates the slope of the apparently linear decline (ko)of concentrations from the values of Co, Km,and Vm.This indicates the hybrid nature of ko.It is pointed out that if a metabolite is formed by Michaelis-Menten kinetics, then (a)one would not expect linear plots of cumulative amount of metabolite excreted in the urine vs. time, and (b)the plasma clearance of the drug will change with dose, and the plasma clearance of the drug would be expected to be different following administration of the same dose in a rapidly available and a slowly available dosage form. The distortion in parameter values when data arising from Michaelis-Menten kinetics are evaluated by classical linear pharmacokinetics is indicated.

Pilot study of zonisamide (1, 2-benzisoxazole-3-methanesulfonamide) in patients with refractory partial seizures

Summary: A new anticonvulsant compound, zonisamide (1,2 benzioxazole‐methanesulfonamide), was studied in 10 adults with medically refractory partial seizures. Following a single oral dose of 400 mg, peak plasma levels occurred an average of 2.8 h after dosing, and the mean clearance from plasma was 2.34 L/h. Whole blood concentrations were high than plasma concentrations because of red blood cell binding. steady‐state plasma concentrations were high than predicted from a linear kinetic model. In most patients, seizure frequency was reduced after zonisamide was substituted for a standard antiepileptic drug. Dose‐related reversible side effects in the central nervous and gastrointestinal system were observed. Most patients tolerated doses between 5.2 and 12.5 mg/kg/day.

Pharmacokinetics of ibuprofen in man. I. Free and total area/dose relationships

Ibuprofen kinetics were studied in 15 subjects after four oral doses. Plasma levels of both total and free ibuprofen were measured for 12 hr, and urine was collected for 48 hr after the doses. All subjects showed a nonlinear relationship between dose and total ibuprofen plasma AUC. Free ibuprofen plasma AUC, however, was linearly related to the dose, suggesting that oral clearance based on free drug was dose independent. Urinary recovery data indicated that efficiency of absorption was dose independent.

Blood ethanol concentrations during and following constant‐rate intravenous infusion of alcohol

Blood ethanol concentrations were determined in 7 subjects during and subsequent to a 2‐hr constant‐rate intravenous infusion of ethyl alcohol (8% V/V). Eight to 10 capillary blood samples were collected during the infusion and 10 to 21 samples were obtained after the infusion ceased. Thus, the total time course of blood ethanol concentrations in man was defined, both during and postirifusion. Blood ethanol concentration data from each of 6 subjects were fitted simultaneously to the two equations for the one‐compartment open model with zero order input and Michaelis‐Menten elimination kinetics. The average Vm [0.232 mg/(ml × hr)] and Km [0.0821 mg/ml] obtained from these fittings correspond very closely with corresponding values estimated by the fitting of all the mean concentration‐time data obtained following oral administration of 4 different doses of ethanol to 8 other fasting subjects in another study. A disproportionate increase in area under the concentration‐time curve with increase in dose (gmlkg) was observed in a single subject who was infused with equal volumes of a 4% and an 8% (V/V) ethanol solution at the same constant rate.

In Vitro Radiation Resistance Among Cell Lines Established From Patients With Squamous Cell Carcinoma of the Head and Neck

Twenty‐five squamous cell carcinoma (SCC) cell lines from 20 patients with head and neck cancer were assessed for radiosensitivity in vitro using a 96‐well plate assay. Four non‐SCC lines were also tested. Radiation sensitivity of individual cell lines was compared using the area under the survival curve (AUC) as a measure of the mean inactivation dose. Tumor lines were tested with either a cobalt‐60 (60Co) γ‐irradiator having a dose rate of 100 cGy/minute or with a 4‐meV photon beam having a dose rate of 200 cGy/minute. The mean AUC of the 25 SCC cell lines was 188 ± 7 (SEM) cGy (range, 100 to 250 cGy) whereas the four non‐SCC lines had a mean AUC of 225 ± 9 cGy. The SCC cell lines with mean inactivation dose values greater than 188 cGy were classified as relatively radioresistant whereas those with values less than 188 cGy were considered relatively radiosensitive. In seven cases SCC cell lines were derived from patients who had already received radiation therapy. In four of these cases the tumor cell lines were radioresistant (AUC, 210 to 250) but in the other three cases the tumor lines were radiosensitive (AUC, 160 to 180). Thus, failure of a tumor to respond to radiation did not always select for radioresistant cells. The mean of the AUC for cell lines from previously irradiated patients (197 ± 11 cGy) did not differ significantly from that of the cell lines from patients who received no prior radiation therapy (182 ± 9 cGy). However, among radiation‐resistant lines those from the four previously irradiated patients were significantly more resistant (mean AUC = 235 ± 9) than seven other radioresistant lines from nonirradiated patients (mean AUC, 208 ± 4) (P = 0.0194). In four cases more than one cell line was derived from different tumor specimens in the same patient. In each of these cases the lines from the same patients were similar to one another in their degree of radioresistance. Based on these observations the authors conclude that the degree of in vitro radiation resistance is an inherent property of some squamous cell tumors.

pH-Related Changes in the Absorption of Dipyridamole in the Elderly

The bioavailability of dipyridamole, a poorly soluble weak base, was evaluated in 11 healthy, older subjects (≥65 years), 6 with a low fasting gastric pH (control) and 5 with a fasting gastric pH > 5 (achlorhydric), in a randomized, crossover design. Subjects received 50 mg dipyridamole as a single oral dose both with and without pretreatment with 40 mg famotidine (control subjects) or 1360 mg glutamic acid HC1 (achlorhydric subjects). Gastric pH was monitored by Heidelberg radiotelemetric capsule. Gastric emptying of 99mTc-radiolabeled orange juice was measured. Gastric pH appeared to be a primary determinant in dipyridamole absorption in the elderly. Elevated gastric pH resulted in compromised dipyridamole absorption compared to low-gastric pH conditions in all cases. The administration of glutamic acid hydrochloride to achlorhydric subjects prior to the dose of dipyridamole corrected for the decreased Cmax and AUC(0–36) exhibited in achlorhydric subjects without pretreatment. Tmax and ka were slower in achlorhydrics, although pretreatment with glutamic acid HC1 tended to normalize these parameters. Based on these results, it would be beneficial for achlorhydrics to take glutamic acid hydrochloride prior to taking dipyridamole and other medications which need a low gastric pH for complete absorption. The administration of 40 mg famotidine was successful in elevating the gastric pH to >5 in all subjects and maintained it at >5 for at least 3 hr in all subjects tested. The lack of differences in Cmax and AUC(0–36) with significant differences in Tmax and ka indicated that control subjects after treatment with famotidine may serve as an adequate model for achlorhydrics with respect to the extent of absorption, but not with respect to the rate of absorption. Gastric emptying of a nutrient liquid was significantly slower in achlorhydric subjects than in control subjects. Finally, fasting serum gastrin appeared to be a relatively reliable and easy method for screening for achlorhydria in the elderly.

Quantitaton of rate of gastrointestinal and buccal absorption of acidic and basic drugs based on extraction theory

Equations have been derived which quantitatively describe the rate of gastrointestinal and buccal absorption of acidic and basic drugs as a function of pH of aqueous lumenal contents and time. The equations have been used to fit observed data in the literature, and the estimated parameters are reported. An equation which describes the renal clearance of an acidic or basic drug as a function of urinary pH is also derived. In essence, the equations quantitate the pH-partition hypothesis and explain most, if not all, related observed data in the literature. The results suggest that the aqueous diffusion layer may not rate-limit absorption of monomeric drug molecules but that absorption is rate-limited by transfer of drug out of the membrane in vivo.

Pharmacokinetics of diphenhydramine in man

Plasma levels and urinary excretion of diphenhydramine were measured after administration of three single 50-mg doses of diphenhydramine hydrochloride to two healthy male volunteers as an intravenous infusion, an oral solution, and a commercially available capsule. A large first- pass effect was evident from the data, with about 50% of the drug being metabolized by the liver before it reached the general circulation. The drug in solution given orally appeared to be fully available to the hepatoportal system, and the availability of diphenhydramine from the capsule was about 83% relative to the solution in one subject and 100% in the other subject. Cumulative amounts of unchanged diphenhydramine excreted in the urine were less than 4% of the administered dose. Both subjects went to sleep at the end of the 1-hr intravenous infusion, but were only drowsy following the oral treatments.