Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism.

In experimental animals, injection of gram-negative endotoxin (LPS) decreases hepatic cytochrome P450-mediated drug metabolism. To evaluate this phenomenon in a human model of gram-negative sepsis, LPS was administered on two consecutive days to healthy male volunteers during which time a cocktail of antipyrine (AP-250 mg), hexobarbital (HB-500 mg), and theophylline (TH-150 mg) was ingested and the apparent oral clearance of each drug determined. Each subject had a control drug clearance study with saline injections. In the first experiment, six subjects received the drug cocktail 0.5 h after the first dose of LPS. In the second experiment, another six subjects received the drug cocktail 0.5 h after the second dose of LPS. In both experiments, LPS caused the expected physiologic responses of inflammation including fever with increases in serum concentrations of TNF alpha, IL-1 beta, IL-6, and acute phase reactants. In the first experiment, only minor decreases in clearances of the probe drugs were observed (7-12%). However in the second experiment, marked decreases in the clearances of AP (35, 95% CI 18-48%), HB (27, 95% CI 14-34%), and TH (22, 95% CI 12-32%) were seen. The decreases in AP clearance correlated with initial peak values of TNF alpha (r = 0.82) and IL-6 (r = 0.86). These data show that in humans the inflammatory response to even a very low dose of LPS significantly decreases hepatic cytochrome P450-mediated drug metabolism and this effect evolves over a 24-h period. It is likely that septic patients with much higher exposures to LPS have more profound inhibition of drug metabolism.

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.

Age-associated stereoselective alterations in hexobarbital metabolism.

This clinical investigation was designed to study the influence of age on stereoselective drug disposition using hexobarbital as a model marker. The disposition of hexobarbital enantiomers was investigated in 10 young and 10 elderly, healthy male volunteers. Mean oral clearance (+/- SD) of d-hexobarbital (1.9 +/- 0.5 vs. 1.7 +/- 0.3 ml/min/kg; P greater than 0.05) did not differ significantly between the young and elderly subjects, respectively. However, despite wide intersubject variability, l-hexobarbital mean oral clearance (+/- SD) was approximately twofold greater in the young than in the elderly subjects (16.9 +/- 11.9 vs. 8.2 +/- 3.2 ml/min/kg; P less than 0.05). This resulted in a significantly greater enantiomeric oral clearance ratio in the young when compared with the elderly subjects (8.3 +/- 3.4 vs. 4.7 +/- 1.4; P less than 0.01). No significant difference (P greater than 0.05) in pharmacologic response after hexobarbital administration was found between the two groups. Demonstration of an age-related preferential decline in metabolism of one enantiomer over another has not been reported previously for any racemic drug in animals or humans.

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.

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.

The effect of endotoxin administration on the pharmacokinetics of chlorzoxazone in humans.

OBJECTIVE: Inflammation induced by Escherichia coli lipopolysaccharide alters the clearance of several hepatically eliminated drugs. Extensive rat liver research has shown CYP2E1 down-regulation after lipopolysaccharide administration. To further investigate this phenomenon in humans, lipopolysaccharide was administered to healthy male volunteers and chlorzoxazone was used as a CYP2E1 probe drug. METHODS: Twelve healthy men were given 500 mg oral chlorzoxazone after two daily lipopolysaccharide doses (20 endotoxin units/kg/day) and again after administration of saline solution in this balanced crossover study. Serum and urine chlorzoxazone and 6-hydroxychlorzoxazone were quantified, as well as cytokine and C-reactive protein levels. RESULTS: Lipopolysaccharide produced the expected induction of the acute-phase response shown by elevations in tumor necrosis factor, interleukin-6, C-reactive protein, and temperature. Lipopolysaccharide treatment failed to produce a significant change in the chlorzoxazone oral clearance (4.4 +/- 0.9 mL/min/kg for lipopolysaccharide versus 4.2 +/- 1.4 mL/min/kg for control) or the 6-hydroxychlorzoxazone formation clearance (2.8 +/- 0.65 mL/min/kg for lipopolysaccharide versus 2.5 +/- 0.9 mL/min/kg for control). The high intersubject variabilities in oral clearance and formation clearance were not accounted for by changes in protein binding, cytokine, or C-reactive protein values. In contrast, a significant increase in the 6-hydroxychlorzoxazone glucuronide renal clearance was observed (7.5 +/- 1.37 mL/min/kg for lipopolysaccharide versus 6.1 +/- 1.7 mL/min/kg for control). CONCLUSIONS: This study showed that the inflammatory response to lipopolysaccharide (20 endotoxin units/kg/day for 2 days) in humans does not consistently alter chlorzoxazone hepatic metabolism. However, the significant increase in renal clearance of the glucuronidated metabolite suggests that renal tubular secretion may be increased in humans with acute endotoxemia.

Age and propranolol stereoselective disposition in humans.

The apparent oral clearance of S(-)- and R(+)-propranolol as a function of age was evaluated in 53 healthy male volunteers (age range, 21 to 84 years) after a single 40 mg oral dose of the racemic mixture. No significant age-associated change in the total (bound plus unbound) and unbound S(-) and R(+) apparent oral clearance was observed (p greater than 0.05). Stereoselectivity in apparent oral clearance (both total and unbound) remained unaffected by advancing age (p greater than 0.05). The relationship between age and propranolol enantiomer plasma protein binding was also evaluated in 70 subjects, 53 of whom were from this study (age range, 21 to 89 years). Plasma free fractions for S(-)- and R(+)-propranolol were unchanged with increasing age (p greater than 0.05), even though the binding was stereoselective (plasma free fractions for R(+) greater than plasma free fractions for S(-); p less than 0.05). The findings from this relatively large and extensive study indicate that age does not influence the stereoselective disposition of propranolol.

Age and beta-adrenergic receptor sensitivity to S(-)- and R,S(+/-)-propranolol in humans.

The relationship between age and beta-adrenergic receptor sensitivity to the pharmacologically active S(-) enantiomer and the racemic mixture of propranolol was evaluated in 46 healthy male subjects (age range, 24 to 89 years). The in vivo apparent dissociation constants for S(-)- and R,S(+/-)-propranolol were determined on the basis of the unbound steady-state plasma concentration of each and the dose of isoproterenol needed to increase the heart rate of the subjects by 25 beats/min in the absence (I25) and then in the presence of a continuous propranolol infusion. The I25 was significantly correlated with age (r = 0.700, p less than 0.05). The apparent dissociation constant for S(-)- and R,S(+/-)-propranolol demonstrated a significant, although weak, increase with advancing age (r = 0.403 and r = 0.396, respectively; p less than 0.05). Although these findings confirm those of other studies, beta-receptor sensitivity to propranolol was only modestly decreased with age in this study.

The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screening costs and influence on clinical outcomes in psychiatry.

OBJECTIVES: This study examined factors that affect cost, reliability, and the value of determining the cytochrome P450 2D6 (CYP2D6) polymorphism in clinical practice. STUDY DESIGN: The method of deoxyribonucleic acid isolation, sample preparation, oligonucleotide primers, and polymerase chain reaction procedures were scrutinized for their effect on CYP2D6 genotyping efforts. The determination of the CYP2D6 A, B, D, E, and T alleles was used to identify the deficiency in CYP2D6 expression in 161 individuals phenotyped for CYP2D6 activity with dextromethorphan. The CYP2D6 genotype was assessed in 74 outpatients who had received diagnoses of depression. Eighteen of these patients were screened because of an adverse response to a tricyclic or antidepressant known or suspected to be a CYP2D6 substrate. RESULTS: The CYP2D6 A, B, C, D, E, and T alleles could be detected in 13 hours at a cost of $84 per sample by judicious selection of conditions and procedures. The genotype provided an accurate predictor of CYP2D6 expression in all 134 subjects who expressed the enzyme and in all 27 unrelated individuals phenotyped as deficient in CYP2D6 activity. In the patient group that experienced adverse effects, 44% of all CYP2D6 gene copies contained the A, B, D, E, or T allele(s) associated with inactive CYP2D6 expression. This was more than twice the rate for the occurrence of mutant alleles in the other 56 psychiatric patients (21%) and in 80 random subjects from the general population (20%; p < 0.05). CONCLUSIONS: Screening psychiatric patients for CYP2D6 expression may distinguish metabolic-based therapeutic problems from drug sensitivity caused by other mechanisms.

Cytochrome P450 and antioxidant activity in interleukin-6 knockout mice after induction of the acute-phase response.

Hepatic cytochrome P450 (CYP) expression and antioxidant activity have been shown to decrease following endotoxin (lipopolysaccharide [LPS]) or proinflammatory cytokine administration. Using mice deficient in interleukin-6 (IL-6), the role of IL-6 in the regulation of hepatic CYP activity, glutathione (GSH) metabolism, and catalase (CAT) activity was analyzed after LPS administration. Administration of LPS produced comparable decreases in hepatic CYP3A activity in WT B6x129 (WT) mice and IL-6 knockout mice. No decrease was observed for CYP2D9 activity after LPS administration in either WT or IL-6 knockout mice. LPS administration significantly increased hepatic and renal CYP2E1 and CYP4A activity in WT mice, with no effect in IL-6 knockout mice. CYP2A12 activity increased in IL-6 knockout, mice with no change in WT mice after LPS administration. LPS administration had no significant effect on hepatic GSH reductase, GST peroxidase, GSH-S-transferase (GST), or total GSH in either WT or IL-6 knockout. However, hepatic CAT activity was significantly reduced in WT mice after LPS administration, with no effect in IL-6 knockout mice. These results support IL-6 as a critical mediator of the effects of LPS on specific hepatic and renal CYP activities and hepatic CAT activity.

Cefetamet pivoxil clinical pharmacokinetics.

Cefetamet pivoxil is an orally absorbed prodrug ester of the microbiologically active cephalosporin, cefetamet. The prodrug ester is completely hydrolysed to the active compound cefetamet on its first pass through the gut wall, the liver or both. Cefetamet is classified as a third generation cephalosporin with excellent activity against streptococci, Enterobacteriaceae, Neisseria and Haemophilus species. It has enhanced stability against beta-lactamases compared with penicillins and first and second generation cephalosporins. The antibacterial spectrum is comparable with that of cefotaxime except for its poor activity against staphylococci. Following a 20-minute zero-order intravenous infusion, cefetamet had a rapid distribution phase followed by a monoexponential decline. The average pharmacokinetic parameters from 152 healthy volunteers were: total body clearance 136 ml/min (8.16 L/h); renal clearance 119 ml/min (7.14 L/h); nonrenal clearance 17 ml/min (1.02 L/h); volume of distribution at steady-state 0.29 L/kg; terminal elimination half-life 2.2 hours; 88% of the dose recovered in the urine. Cefetamet is not extensively bound to plasma proteins. Consequently, these data indicate that cefetamet is predominantly eliminated unchanged by the kidney via glomerular filtration with possibly a minor component of tubular secretion. Cefetamet has a relatively small apparent volume of distribution consistent with that of other beta-lactam antibiotics. Results following ascending intravenous doses of cefetamet in healthy young male volunteers demonstrated that the pharmacokinetics of intravenous cefetamet are independent of the dose. The absolute bioavailability of cefetamet tablets following oral cefetamet pivoxil administration is enhanced by the presence of food. Under fed conditions, 50 to 60% of the final oral dose is absorbed into the systemic circulation. This food effect is observed when cefetamet pivoxil is administered within 1 hour of a meal. Food also produces a slight delay in the time to reach peak plasma concentrations of this drug. Changes in fluid volume intake with cefetamet pivoxil administration have no effect on the bioavailability of this drug. Similar absorption characteristics have been observed for all of the tablet dosage formulations studied during clinical development. The absolute bioavailability of the final syrup dosage formulation was between 38 and 47%. Little improvement in the bioavailability of this preparation has been observed with food. The absorption and disposition of cefetamet in human subpopulations [i.e. children, elderly (< 75 years of age), renal impairment, liver disease and patients taking concomitant drugs] have been studied extensively. Only impaired renal function appears to significantly alter the elimination of this drug.(ABSTRACT TRUNCATED AT 400 WORDS)

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 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.

Clinical pharmacokinetics of verapamil.

Verapamil is widely used in the treatment of supraventricular tachyarrhythmias as well as for hypertension and control of symptoms in angina pectoris. Unlike other calcium antagonists, detailed pharmacokinetic data are available for verapamil. Plasma concentrations of verapamil appear to correlate with both electrophysiological and haemodynamic activity after either intravenous or oral drug administration, although considerable intra- and intersubject variation has been found in the intensity of pharmacological effects resulting at specific plasma drug levels. Verapamil is widely distributed throughout body tissues; animal studies suggest that drug distribution to target organs and tissues is different with parenteral administration from that found after oral administration. The drug is eliminated by hepatic metabolism, with excretion of inactive products in the urine and/or faeces. An N-demethylated metabolite, norverapamil, has been shown to have a fraction of the vasodilator effect of the parent compound in in vitro studies. After intravenous administration, the systemic clearance of verapamil appears to approach liver blood flow. The high hepatic extraction results in low systemic bioavailability (20%) after oral drug administration. Multicompartmental kinetics are observed after single doses; accumulation occurs during multiple-dose oral administration with an associated decrease in apparent oral clearance. Norverapamil plasma concentrations approximate those of verapamil following single or multiple oral doses of the parent drug. Because of the complex pharmacokinetics associated with multiple-dose administration and the variation in individual patient responsiveness to the drug, 'standard' dosing recommendations are difficult to determine; use of verapamil must be titrated to a clinical end-point. Further, the potential for alteration in verapamil's disposition by the presence of hepatic dysfunction or cardiovascular disorders which result in altered hepatic blood flow is only now becoming apparent. A potentially toxic interaction has been reported between verapamil and digoxin, in which renal excretion of the glycoside is impaired, but the true clinical significance of this remains debatable. Combination therapy with verapamil and beta-adrenoceptor blocking compounds has been advocated by some investigators, but may be hazardous because of the additive negative inotropic and chronotropic effects inherent in both agents.

Pharmacokinetics of calcium-entry blockers.

Effective use of drugs in therapy depends not only on clinical acumen but also on the availability of relevant pharmacokinetic and pharmacodynamic data. Such information assists in development of safe dosing regimens, prediction of abnormal handling of drugs in states of disease and disorder and anticipation of drug interactions. For the calcium-entry blocking agents now available in the United States (verapamil, nifedipine and diltiazem), these data appeared well after clinical patterns of use evolved. Nonetheless, their relevance continues to be demonstrated by the dependence of each agent on intact liver blood flow and function for normal rates of elimination; by the nonlinear kinetic characteristics for verapamil and diltiazem (and probably for nifedipine, as well) and the derivative implications for decreased dosing frequency requirements; and by observations now appearing on the relation between plasma drug levels and drug effects, both therapeutic and toxic. Such data are discussed herein, with emphasis on those aspects that impact on the clinical use of the calcium-entry antagonists.

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.

The effect of acute and chronic renal failure on theophylline clearance.

Theophylline total body clearance was measured in 29 anuric, chronic obstructive pulmonary disease patients with acute or chronic renal failure during a continuous intravenous infusion. They were divided into two groups depending on the absence (group 1, N = 16) or presence (group 2, N = 13) of congestive heart failure and compared to normal renal function control patients with similar disease states. All study and control patients smoked cigarettes. The theophylline mean total body clearance values (+/- S.D.) for group 1 were 68.0 +/- 14.5, 64.5 +/- 12.9, and 62.6 +/- 17.3 ml/kg.hr for acute renal failure patients, uremic chronic renal failure patients, and control patients, respectively. For group 2, the corresponding values were 25.6 +/- 5.1, 28.6 +/- 8.7, and 27.4 +/- 12.9 ml/kg.hr. There was no significant difference between study and control patients in either group 1 or group 2 (P greater than 0.05, one-way analysis of variance). Since total body clearance determines the steady-state concentration of a drug after repeated administration, theophylline doses do not need to be reduced in acute renal failure or uremia patients.

Pulmonary function in the elderly: response to theophylline bronchodilation.

This clinical investigation was designed to characterize the pharmacologic response to theophylline in elderly individuals. Incremental theophylline plasma concentrations (0, 5, 10, 15, and 20 mcg/mL), achieved through dose escalation of intravenous aminophylline, were correlated with pulmonary airway responses in ten young and ten elderly male asthmatic volunteers. The older group had lower baseline pulmonary function values, suggestive of a greater degree of baseline airways obstruction. Despite wide intersubject variability, the elderly subjects demonstrated a lower absolute change in bronchodilator response to equal concentrations of theophylline than did their younger counterparts (P less than .05). A progressive increase in heart rate was noted with increasing theophylline concentrations, but no significant difference in heart rate change between groups was detected (P greater than .05). Whether the difference in theophylline induced bronchodilator response observed in the young and elderly groups is due to a difference in age or in severity of airway obstruction is yet unknown.

The pharmacokinetics of oral isradipine in normal volunteers.

The pharmacokinetics and relative bioavailability of oral isradipine, a dihydropyridine calcium channel blocking agent, were determined in 42 normal male volunteers participating in two separate studies. Eighteen of the subjects received 2.5-, 5-, and 10-mg oral doses of isradipine solution (Study 1). The remaining 24 subjects received four 2.5-mg capsules, one 10-mg capsule, and 10 mg of isradipine as an oral solution (Study 2). Venous blood samples were obtained prior to and at frequent intervals after administration of each dose form. Plasma isradipine concentrations were measured by radioimmunoassay. No significant dose effect occurred with respect to any pharmacokinetic parameter except AUC and Cmax in Study 1. In Study 2, Cmax, tmax, and MRT were significantly different after the solution compared with the capsular formulations. The respective pharmacokinetic parameters (mean +/- SD) for the 10-mg solution and 10-mg capsule in Study 2 were time to maximum concentration, 0.40 +/- .28 and 1.57 +/- 0.44 hours; oral clearance, 284.9 +/- 105.3 and 317.0 +/- 138.4 L/hr; elimination half-life, 5.36 +/- 1.8 and 6.63 +/- 2.4 hrs, respectively. Headache, dizziness, and tachycardia were the most frequent adverse effects in both studies.

The effects of renal function on the disposition of isradipine.

The effect of renal function on isradipine kinetics was examined in four groups of subjects (N = 55) who had normal or impaired renal function. Each subject received isradipine orally as a 10-mg capsule. Serial blood samples were obtained from 0 to 48 hours postdose and the isradipine plasma concentrations determined by radioimmunoassay. Kinetic parameters, Cmax, lambda 3, t 1/2, AUC, CL'o (oral clearance), and CLo (oral clearance standardized to body weight) were determined. Marked intersubject variability of the pharmacokinetic parameters was observed. No statistically significant differences (P greater than .05) were found for AUC, Cl'o, and Clo parameters when renal impairment groups were compared with controls. AUC values were lower (P less than .05), however, for the group with severe renal function impairment than for groups with mild or moderate renal function impairment. No significant correlations (r = -.23, P greater than .05; and r = .13, P greater than .05, respectively) were found between creatinine clearance (CLCR) and CLo and between age and CLo. Considering the interpatient variability in isradipine disposition and the lack of significant differences in CLo between groups, no clear-cut dosing regimen alterations, based on single-dose data, are warranted in renal impairment.