Age and phenytoin kinetics in adult epileptics.

Michaelis-Menten parameters for rate of drug metabolism (Vmax) and serum concentration at which metabolism is half of Vmax (Km) were determined in 92 adult epileptic patients taking phenytoin who were 21 to 78 yr old. The patients received no known inhibitors or inducers of phenytoin metabolism. Results of physical examinations and tests of liver function and total bilirubin and albumin concentration were normal. Divided into age groups, Vmax values were 7.5 +/- 2.2, 6.6 +/- 1.8, and 6.0 +/- 1.9 mg/kg/day for the 20- to 39-, 40- to 59-, and 60- to 79-yr-old subjects, respectively. Values for those in the 60- to 79-yr-old group were substantially less than those for the youngest subjects (20- to 39-yr-olds; P less than 0.05). Linear regression analysis indicated a decline in Vmax with age (r = 0.518). Km values did not appear to be influenced by age; means ranged from 5.4 to 5.8 microgram/ml. As a result of these changes, the 60- to 79-yr-old group would require, on the average, 21% less phenytoin per day than the 20- to 39-year-olds to maintain a steady-state concentration of 15 microgram/ml. First doses can be based on these data and maintenance doses arrived at based on clinical response.

Verapamil inhibits ethanol elimination and prolongs the perception of intoxication.

Ten young healthy men received verapamil (80 mg every 8 hours for 6 days) or placebo in a blinded, randomized, crossover design. On the sixth day, ethanol was administered as a single oral dose (0.8 gm/kg), and blood samples were collected over the following 12 hours for determination of verapamil, norverapamil, and ethanol concentrations. Compared with placebo, verapamil increased the peak blood ethanol concentration (106.45 +/- 21.40 to 124.24 +/- 24.74 mg/dl, p less than 0.05) and area under the ethanol concentration versus time curve (365.67 +/- 93.52 to 475.07 +/- 97.24 mg.hr/dl, p less than 0.005). Verapamil areas under the concentration versus time curves (AUC) were positively correlated (r = 0.71, p less than 0.05) to increased ethanol blood AUC values. Each subject's perception of ethanol intoxication was measured by use of a simple visual analog scale. Compared with placebo, verapamil significantly increased area under the effect versus time curve (10.19 +/- 7.6 to 13.83 +/- 7.81 cm.hr, p less than 0.002) but did not change the peak effect or time to peak effect. Ethanol effect versus concentration plots were not significantly different between verapamil and placebo treatment phases when increased ethanol concentrations during verapamil therapy were taken into account. The findings of our study suggest that verapamil significantly inhibits ethanol elimination, resulting in elevated blood ethanol concentrations that prolong the intoxicating effects of alcohol.

Theophylline clearance: effect of marked obesity.

Total body clearance (ClT) of theophylline was examined in 12 markedly obese patients and related to total body weight (TBW) and ideal body weight (IBW). Patients were infused with aminophylline continuously and evaluated at steady state. Total body clearances of theophylline were 29.5 +/- 7.8 ml/hr/kg TBW and 58.8 +/- 15.9 ml/hr/kg IBW. In patients with congestive heart failure (CHF) (N = 4) theophylline ClT was 19.7 +/- 1.9 ml/hr/kg TBW or 47.7 +/- 8.3 ml/hr/kg IBW while in those with no CHF (N = 8) clearance was 34.5 +/- 3.5 ml/hr/kg TBW or 64.3 +/- 16.2 ml/hr/kg IBW. Acute renal failure did not appear to alter theophylline ClT in two patients (one with and one without CHF). Mean theophylline ClT closely approximated that of a normal population when corrected for IBW, but there was a much stronger correlation between theophylline ClT and weight when corrected for TBW. Our data suggest that maintenance doses of theophylline in markedly obese patients with CHF should be based on a theophylline ClT of 19.7 ml/hr/kg TBW and of 34.5 ml/hr/kg TBW in those with no CHF.

Diurnal variation in valproic acid clearance.

Diurnal variation in total and unbound valproic acid concentrations was measured at steady state in seven healthy men and three healthy women after 250-mg oral doses every 12 hr. Total average steady-state concentration (Css) during the morning dosage interval was 50.4 mg/l. During the evening dosage interval, total Css was 45.7 mg/l. Unbound Css was also less during the evening (2.9 and 3.4 mg/l). These changes were due to higher total and unbound clearance rates during the evening dosage interval. Total peak concentrations were lower (56.8 and 64.3 mg/l) and time of peak concentrations slightly longer (2.2 and 1.8 hr) during the evening. There was marked interindividual variability in all these changes. For best reproducibility of steady-state valproic acid concentrations, our results suggest that total and unbound levels be drawn at the same time of day.

Influence of long-term infusions on lidocaine kinetics.

Lidocaine kinetics were examined during continuous infusions in five healthy subjects using stable isotope lidocaine labeled with two deuterium atoms. During phase 1, lidocaine and stable isotope lidocaine (50 mg IV each) were given as a bolus to confirm that the two species were kinetically identical. Phase 2 consisted of a long-term (30 hr) lidocaine infusion designed to produce a steady-state concentration equal to 1.5 microgram/ml. Twenty-four hours into the infusion, stable isotope lidocaine (50 mg) was given as an intravenous bolus and kinetic parameters were calculated. Phase 3 differed from phase 2 in that target steady-state lidocaine concentration was 4 microgram/ml and the stable isotope lidocaine dose was reduced to 40 mg. A gas chromatograph-mass spectrometer was used to determine lidocaine and stable isotope lidocaine serum concentrations. Compared to phase 1, clearance decreased (P less than 0.05) and half-life increased (P less than 0.025) during phases 2 and 3. The volume of distribution at steady-state remained constant during all three phases. Lidocaine cumulated in serum during long-term infusions in all five patients; repeated decreases in infusion rate were necessary to avoid exceeding desired target concentrations in phases 2 and 3.

Valproic acid clearance: unbound fraction and diurnal variation in young and elderly adults.

Six young (22 to 25 years old) and six elderly (60 to 88 years old) healthy adults took valproic acid, 250 mg by mouth, at 8 am and 8 pm for 5 days. On the fifth day, blood samples were drawn over each dosage interval. Both young and elderly subjects exhibited diurnal variability. Total and unbound clearances in the young and elderly subjects were about 10% and 15% higher during the evening. These changes led to lower total and unbound steady-state and peak concentrations during the nighttime dosage interval. There were no differences in total steady-state concentrations and kinetics computed from total concentrations between the young and elderly, but there were differences in unbound steady-state concentrations and kinetics. Unbound clearances were 65% lower, which resulted in unbound steady-state concentrations 67% higher in the elderly. The average unbound fractions in the elderly and young were 10.7% and 6.4%. To minimize the influence of diurnal variability, drug concentrations should be determined at the same time each day. Total valproic acid concentration data may be less useful in elderly patients; unbound concentrations may be more reliable in this population.

Single and multiple doses of oral cimetidine do not change liver blood flow in humans.

Liver blood flow was measured in 10 healthy men for 6 hours after single (300 mg) and multiple (300 mg every 6 hours for 5 days) oral doses of cimetidine. Blood flow measurements were determined in the superior mesenteric and hepatic arteries and in the intrahepatic branches of the portal and hepatic veins by use of a duplex Doppler ultrasound technique. Compared with baseline measurements obtained before drug administration, cimetidine treatment did not change blood flow in any of the four blood vessels. Cimetidine serum concentrations and pharmacokinetic parameters were similar to those reported in other studies conducted in healthy adults. The findings of this study indicate that single and multiple 300 mg doses of oral cimetidine do not change liver blood flow.

Tobramycin pharmacokinetics in morbidly obese patients.

Tobramycin kinetics were examined in 9 morbidly obese women following a single intravenous (120 mg) bolus. After the injection, serum elimination conformed to a 2-compartment open model with alpha and beta t1/2s of 0.285 and 2.1 hr. The volume of distribution (Varea) was determined to be 0.44 1/kg ideal body weight (IBW) and 0.20 1/kg total body weight (TBW). To normalize Varea to 0.26 1/kg, 58% of the patients' adipose weight (TBW -- IBW) must also be taken into account.

Ethosuximide kinetics: possible interaction with valproic acid.

Ethosuximide kinetics were determined in six normal healthy adults after a single dose (phase 1) and at steady-state (phase 2). After the completion of phase 2, valproic acid was added to the ethosuximide regimen (phase 3) to assess the possibility of drug interaction. Between phases 1 and 2 total clearance fell from 13.1 to 11.1 ml/hr/kg (P less than 0.05) and nonrenal clearance fell from 10.1 to 8.3 ml/hr/kg (P less than 0.05). When valproic acid was added (phase 3) there was no further change in total or nonrenal clearance (11.2 and 8.3 ml/hr/kg). To assess the possibility of nonlinear ethosuximide kinetics a review was conducted of patients who received ethosuximide as sole therapy for absence seizures. Of 106 patients, 10 met the required criterion that defined steady state. Data from seven of the 10 patients showed evidence of a nonlinear relationship when steady-state ethosuximide concentrations were plotted against dose.

Changes in antipyrine and indocyanine green kinetics during nifedipine, verapamil, and diltiazem therapy.

Ten healthy subjects received oral antipyrine and intravenous indocyanine green (ICG) alone and after 5 days of oral nifedipine, diltiazem, and verapamil. Antipyrine clearance decreased during verapamil (range 4% to 26%) and diltiazem (6% to 24%) therapy (P less than 0.001) but did not change during nifedipine treatment. Antipyrine t1/2 also increased during verapamil and diltiazem treatment (P less than 0.001). ICG clearance did not change during diltiazem therapy but increased during dosing with nifedipine and verapamil (P less than 0.05). Estimated liver blood flow (derived from ICG clearance and hematocrit) also increased during verapamil (mean 33%) and nifedipine (mean 27%) treatment (P less than 0.05). Drug interactions with other liver-metabolized drugs may occur during therapy with these calcium antagonists. Nifedipine appears to increase liver blood flow whereas diltiazem inhibits oxidative drug metabolism. Drug interactions with verapamil could involve both mechanisms.

Cimetidine clearance in the obese.

Six subjects with normal weight (mean weight = 62 kg) and six obese subjects (mean weight = 140 kg) were given a single intravenous cimetidine infusion of 600 mg over 10 to 15 minutes. Both groups of subjects had normal serum creatinine levels and were matched with respect to age, desirable body weight, height, renal function, and sex. Compared with subjects of normal weight, obese subjects had higher cimetidine systemic (1147 and 637 ml/min) and renal (808 and 318 ml/min) clearances. Volume of distribution at steady state was of the same order for the two groups (82 and 84 L), but the t 1/2 was shorter in the obese group (1.2 and 1.9 hr). Obese subjects had lower cimetidine sulfoxide serum concentrations and greater cimetidine sulfoxide renal clearance (856 and 509 ml/min). Cimetidine systemic clearance and cimetidine sulfoxide renal clearance values were of the same order in the two groups when normalized by the value of weight raised to the 0.76 and 0.5 powers. Under the assumptions of an average weight of 70 kg and that average serum concentrations produced by cimetidine, 300 mg iv every 6 hours, are appropriate, people with normal renal function and body weight usually receive 48 mg/day/weight0.76. This same dosage in obese individuals with normal serum creatinine values should result in the same average steady-state serum concentrations. In our obese subjects, the mean cimetidine dose would have been approximately 500 mg iv every 6 hours.

The effects of oral nifedipine on hepatic blood flow in humans.

Duplex ultrasonography was used to measure changes in hepatic blood flow in 13 healthy volunteers after they received single doses of 10 mg oral nifedipine and placebo. Blood flow was measured in the hepatic artery and branches of the portal and hepatic veins at baseline and 0.3, 0.6, 1, 1.5, 2, 3, 4, and 5 hours after drug administration. Cardiac output was also measured at baseline and 1, 2, and 3 hours after dosing. Blood flow initially increased in all three vessels 0.6 hour after administration of nifedipine (29%, 56%, and 31% in the hepatic artery, hepatic vein, and portal vein, respectively) compared with placebo. Flow rapidly returned to baseline in the hepatic artery and hepatic vein, whereas it appeared to remain elevated through 3 hours in the portal vein. Nifedipine administration resulted in an increase in cardiac output of 26%, 22%, and 14% above placebo at 1, 2, and 3 hours, respectively. No significant differences were detected in the systolic, diastolic, or mean arterial blood pressures after nifedipine or placebo. This study demonstrates that nifedipine increases hepatic blood flow in a transient nature and systemic hemodynamic parameters do not necessarily reflect specific organ responses. The nifedipine-induced change in blood flow should be considered when nifedipine is coadministered with high-clearance drugs, because systemic availability may be increased.

Disposition of drugs in cystic fibrosis. II. Hepatic blood flow.

To determine whether the increased clearance of high extraction-ratio drugs in cystic fibrosis is caused by an increase in hepatic blood flow, the blood flow in main branches of the hepatic vein and portal vein was measured by use of noninvasive duplex ultrasound scanning in 10 adult subjects with cystic fibrosis and in 10 healthy age-, gender-, and height-matched control subjects. No statistically significant differences between subjects with cystic fibrosis and control subjects were detected in either the hepatic vein (217 +/- 103 ml/min for subjects with cystic fibrosis versus 211 +/- 135 ml/min for control subjects) or the portal vein (205 +/- 114 ml/min for subjects with cystic fibrosis versus 190 +/- 101 ml/min for control subjects) blood flows. These data indicate that a large (greater than or equal to 100%) increase in the clearance of high extraction-ratio drugs in patients with cystic fibrosis is unlikely to be primarily caused by an increase in hepatic blood flow. It is probable that alternative mechanisms such as enhanced secretory or metabolic pathways account in large part for increases in clearance of high extraction-ratio drugs.

Interference of oral phenytoin absorption by continuous nasogastric feedings.

Inhibition of phenytoin absorption by continuous nasogastric tube feeding was studied in 20 neurosurgery patients and 5 normal subjects. Ten patients receiving phenytoin suspension 300 mg per day coadministered with continuous nasogastric feedings had a mean phenytoin serum concentration of 2.59 micrograms per milliliter. When the feedings were discontinued, the average concentration rose to 10.22 micrograms per milliliter in 7 days. In 10 other patients stabilized on phenytoin suspension 300 mg per day, the average serum concentration decreased from 9.80 microgram per milliliter to 2.72 microgram per milliliter in 7 days when continuous tube feedings were started. Five normal subjects received a single oral dose of phenytoin suspension alone and while drinking a nasogastric tube feeding preparation orally at a rate of 100 ml per hour; phenytoin serum levels decreased an average of 71.6% when the tube feeding was taken concurrently.

Influence of age on theophylline clearance in patients with chronic obstructive pulmonary disease.

Theophylline total body clearance was calculated in 59 adult patients requiring intravenous aminophylline therapy. Group 1 consisted of 36 chronic obstructive pulmonary disease patients who were cigarette smokers without other conditions known to alter theophylline kinetics (age range: 22 to 79 years). Group 2 consisted of 23 chronic obstructive pulmonary disease patients who were cigarette smokers with a similar degree of congestive heart failure, but free of other characteristics or diseases that affect theophylline disposition (age range: 41 to 81 years). When individual theophylline total body clearance values were plotted against age in each group, poor correlation coefficients were found, indicating that age is not a good predictor of total body clearance of theophylline (group 1: r = 0.101; group 2: r = 0.276). Each group was also broken into 'younger' and 'older' patients. No significant differences in theophylline total body clearance values were found between the younger and older patients for either group I or 2, suggesting that a theophylline dosage reduction is not necessary in cigarette smoking patients over an arbitrary age limit.

Phenytoin Michaelis-Menten pharmacokinetics in Caucasian paediatric patients.

The Michaelis-Menten pharmacokinetic parameters Vmax and Km were calculated for 135 epileptic paediatric patients receiving phenytoin as their only anticonvulsant therapy. Mean Vmax and Km values were 13.95 mg/kg/day and 6.59 micrograms/ml for 0.5 to 3-year-old patients, 10.93 mg/kg/day and 6.82 micrograms/ml for the 4 to 6 year age group, 10.05 mg/kg/day and 6.51 micrograms/ml for the 7 to 9-year-olds, and 8.25 mg/kg/day and 5.69 micrograms/ml for the 10 to 16 year group. Using analysis of variance, the Vmax values were significantly different (p less than 0.01) but the Km values were not. Linear regression analysis of Vmax versus age revealed a significant decline in Vmax with age (r = -0.554; p less than 0.001). A plot of Km versus age showed a poor correlation (r = -0.170) and a large amount of variability. Based on this data, the youngest age group would require on average 62% more phenytoin/kg/day than the oldest age group in order to maintain a steady-state phenytoin concentration of 15 micrograms/ml. Because of these age-related pharmacokinetic differences, phenytoin dosages may require adjustment as paediatric patients become older.

Influence of pharmacokinetic diurnal variation on bioavailability estimates.

The effects of diurnal variation on bioavailability assessments were examined using computer-simulated data based on the changes observed in theophylline kinetics. During one 12-hour dosage interval (noon to midnight), clearance was assumed to be larger than during the other dosage interval (midnight to noon). Oral data was simulated until steady-state occurred. Intravenous bolus data, which represented a stable-isotope pulse dose, was also simulated for both the high and low clearance dosage intervals. When the respective areas under the serum concentration-time curves were compared, the systemic availability (F = AUCpo/AUCiv) during the dosage interval with the larger clearance was greater than 1.0, but during the dosage interval with the smaller clearance it was less than 1.0. When computing the bioavailability of a drug, diurnal variations should be assessed as a potential cause of variation.

Multiple-dose non-linear regression analysis program. Aminoglycoside dose prediction.

The ability of a new multiple-dose non-linear regression analysis program to predict steady-state aminoglycoside peak and trough serum concentrations was evaluated. 30 patients receiving either amikacin (7), gentamicin (10) or tobramycin (13) were studied. A standard method of prediction which requires the collection of 3 or 4 serum samples during a dosing interval and a predictive method which relies upon population-based estimates of pharmacokinetic parameters were compared with the new approach which requires the collection of 2 serum samples. There were no significant differences between the methods which utilised serum concentration data with regard to predictive precision (mean prediction error of about 10%). These methods were more precise than the population-based method (p less than 0.01, mean prediction error 29.1%). None of the methods produced biased estimates. These results indicate that when the regression program is employed, valid estimates of pharmacokinetic parameters and prediction of steady-state serum concentrations can be obtained with fewer serum samples than have been recommended.

Gentamicin pharmacokinetics: effect of aging in patients with normal renal function.

The effects of aging on gentamicin total-body clearance, volume of distribution, and half-life were examined in 173 febrile patients with gram-negative infections. All had normal renal function, normal hematocrit levels, near-ideal body weights, and were not receiving concurrent penicillin therapy. In the 51 patients who were 20-39 years old, the mean clearance of gentamicin was 1.29 ml/min/kg, the volume of distribution was 0.23 l/kg, and the half-life was 2.2 hours. In the 59 patients 40-59 years old, these values were 1.35 ml/min/kg, 0.27 l/kg, and 2.1 hours; in the 63 patients 60-79 years old, they were 1.31 ml/min/kg, 0.26, and 2.4 hours. No significant difference was observed for any of the measures among the three age groups (P less than 0.05, analysis of variance). Linear regression revealed poor correlations between the individual measures and age. Since there is no change in gentamicin pharmacokinetics with aging, dosages do not need to be changed arbitrarily for older patients who have normal renal function.

Procainamide-cimetidine drug interaction in elderly male patients.

Thirty-six hospitalized male patients receiving oral sustained-release procainamide every six hours for the treatment of ventricular arrhythmias were studied at steady-state before and after oral cimetidine 300 mg every six hours for three days. Average age and weight were 73 +/- 12 (SD) years and 76 +/- 10 kg. Patients did not have a myocardial infarction within the last two years or congestive heart failure and had calculated creatinine clearances (CrCl) between 35 and 75 mL/min/70 kg. Ten patients had urine collections that permitted computation of the ratio between the renal clearance of procainamide and CrCl (PA/CrCl) and the renal clearance of n-acetyl-procainamide (NAPA) and CrCl (NAPA/CrCl). The average steady-state procainamide and NAPA concentrations increased 55% and 36%, respectively, during cimetidine treatment (P less than .01). Twelve patients experienced mild to severe symptoms of what may have been procainamide toxicity. Apparent procainamide oral clearance decreased 41% while patients received cimetidine (P less than .01). PA/CrCl and NAPA/CrCl ratios decreased by 33% and 21%, respectively, during cimetidine therapy (P less than .05). Cimetidine therapy given to older male patients taking procainamide can cause steady-state concentrations of procainamide to rise to toxic levels. Patients prescribed this combination should be monitored carefully for adverse side effects.