Variability in pharmacokinetic values for gentamicin, tobramycin, and netilmicin in patients with renal insufficiency.
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Adult↗
Biomedical subjects
G R Matzke
Publications and source records attributed to G R Matzke.
Interindividual and intraindividual variability in labetalol pharmacokinetics.
The between-subject and within-subject variability in the pharmacokinetics of labetalol at steady state were determined. Sixteen nonobese normal volunteers (mean age, 27 years) received five different formulations of labetalol orally on five different occasions every 12 hours for five doses. A 7-day washout separated each administration phase. Plasma concentration-time data for labetalol were obtained over the 24-hour period after the fifth dose in each phase. Labetalol concentrations in plasma were measured using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters for each subject after each study phase were estimated. The mean V beta/F, Vdss/F, TBC/F, t1/2 beta, and AUC tau 0 for each subject ranged between 18.1 and 161.9 L/kg, 7.1 and 53.9 L/kg, 1.3 and 5.72 L/hr/kg, 6.9 and 11.0 hours, and 154 and 520 micrograms.hr/L, respectively, indicating large interindividual variability. Considerable intraindividual variability in each of the pharmacokinetic parameters was also observed. These data indicate that a larger number of subjects will be required to detect "significant" differences in the disposition of labetalol.
Adult↗
Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease.
The pharmacokinetics and pharmacodynamics of codeine and its metabolites codeine glucuronide, morphine, and morphine glucuronide were assessed after the administration of a single 60 mg oral dose of codeine sulfate and a single 60 mg intravenous dose of codeine phosphate in six healthy volunteers and six patients on chronic hemodialysis. Plasma and urine drug and metabolite concentrations were determined by sensitive and specific RIA procedures. Pharmacodynamics were assessed by pupillometry and vital sign determinations. Codeine elimination half-life and mean residence time were increased significantly in the hemodialysis group (18.69 +/- 9.03 hours and 12.77 +/- 7.09 hours, mean +/- SD, respectively) compared with the healthy volunteer group (4.04 +/- 0.60 hours and 3.90 +/- 0.52 hours, respectively). The total body clearance and volume of distribution of codeine were not significantly different between groups. Peak concentrations, times to peak concentrations, and AUCs for the three metabolites were also not significantly different between the groups, in part as a result of significant interpatient variability in the hemodialysis group. Examination of pupillometry and vital sign data did not reveal clinically significant differences in pharmacodynamics between the groups. Adjustment of dosage regimen may be required in some patients with uremia receiving multiple-dose codeine therapy.
Adult↗
Disposition of ceftazidime in surgical patients with intra-abdominal infection.
The disposition of ceftazidime was assessed in 11 surgical patients with suspected intra-abdominal infection. All patients had normal hepatic function, and creatinine clearances ranged from 43 to 186 ml/min. Patients received 2 g of ceftazidime intravenously every 8 h. Trough and peak concentrations in serum were measured on day 2, and trough and postdose concentrations in serum were determined on 10 samples collected during a dosage interval between days 3 and 6 of therapy. Ceftazidime peak and trough concentrations in serum at steady state determined by high-performance liquid chromatography were 257.4 +/- 122.0 (mean +/- standard deviation) and 13.1 +/- 20.6 mg/liter. The serum-concentration-versus-time profile was multiexponential. The elimination half-life, steady-state volume of distribution, and total body clearance were 2.52 +/- 1.39 h, 0.31 +/- 0.12 liter/kg, and 0.11 +/- 0.05 liter/h per kg, respectively. Total predicted body clearance significantly correlated with the measured values (r = 0.868; P = 0.001). The disposition of ceftazidime is dependent on creatinine clearance and is not significantly altered by surgery or acute infectious processes.
Abdomen↗
Pharmacokinetics of cefonicid in patients with skin and skin structure infections.
The disposition of cefonicid (2 g intravenously every 24 h) was assessed in 15 patients with skin and skin structure infections. Trough and peak concentrations in serum were measured on two successive days to verify the attainment of steady state; and 1 trough and 12 postdose values of the concentration in serum were collected on the following day. Cefonicid concentrations in serum were determined by high-performance liquid chromatography. The cefonicid serum concentration versus time profile after intravenous infusion was clearly biexponential in all patients. The terminal elimination half-life determined by nonlinear regression analysis was 4.63 +/- 1.49 h (mean +/- standard deviation). The steady-state volume of distribution and total body clearance were 0.12 +/- 0.04 liter/kg and 0.369 +/- 0.110 ml/min per kg, respectively. These results are comparable to parameters derived from previous studies in noninfected normal volunteers. Thus, the disposition of cefonicid is not altered in patients with severe skin and skin structure infections.
Adult↗
Suprofen-induced uricosuria. A potential mechanism for acute nephropathy and flank pain.
Suprofen, a nonsteroidal anti-inflammatory drug, has been associated with the onset of acute flank pain, hematuria, and transient renal dysfunction after the ingestion of one or two doses, particularly in young males. Potential mechanisms of this nephropathy were evaluated in normal males following ingestion of suprofen (200 mg) on two occasions: the first with ad libitum fluid intake and the second during forced water diuresis. On the first study occasion, creatinine clearance, the fractional excretions of uric acid (FEUA) and sodium (FENa), the urinary concentration of undissociated uric acid, and the urinary excretions of prostaglandins and glomerular and tubular proteins were assessed. On the second occasion, inulin and PAH clearances and FEUA and FENa were determined. Within 90 min after suprofen administration, the FEUA increased from 8.8 +/- 2.6 to 35.5 +/- 9.6% (p less than 0.05). Urine became supersaturated for uric acid during ad libitum fluid intake. Glomerular filtration rate, renal plasma flow, and FENa decreased significantly, while prostaglandin and protein excretions did not change. The findings are consistent with acute uric acid nephropathy as a mechanism of suprofen-induced renal dysfunction.
Acute Disease↗
Clinical trials: a basic bibliography (#44).
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Bibliographies as Topic↗
Single and multiple dose pharmacokinetics of oral ciprofloxacin in elderly patients.
The pharmacokinetics of oral ciprofloxacin were evaluated in 20 elderly patients with serious respiratory tract or musculoskeletal infections after single and multiple dose regimens of 750 mg of drug every 12 h. The single dose phase evaluations were performed on day 1 of therapy (n = 20) while the multiple dose phase evaluations were performed at the end of therapy (n = 11). Serum and urine ciprofloxacin concentrations were determined using high-performance liquid chromatography. Peak serum concentration (Cmax), terminal elimination half-life (t1/2 beta), apparent total body clearance (CL/f) and apparent volume of distribution (Vd/f) were 6.58 +/- 2.88 mg/l, 4.99 +/- 1.79 h, 6.69 +/- 3.73 ml/kg/min, and 2.87 +/- 1.86 l/kg, respectively, during the single dose phase. Only the Vd/f increased significantly during the multiple dose phase (4.40 +/- 3.32 vs. 2.71 +/- 1.53 l/kg, p = 0.047). Although Cmax increased and CL/f decreased markedly after multiple doses (8.83 +/- 2.79 vs. 6.65 +/- 2.28 mg/l, p = 0.057 and 5.61 +/- 2.53 vs. 6.53 +/- 3.03 ml/kg/min, p = 0.074, respectively), these changes were not statistically significant. The results of this study are consistent those previously derived from single dose studies in healthy and mildly-ill elderly subjects, but are markedly different from previous observations in young adult volunteers. Thus, acute illness does not significantly alter the pharmacokinetics of ciprofloxacin in the elderly suggesting that dosage adjustments based on the presence of acute illness do not appear warranted.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Pharmacokinetics of ciprofloxacin in acutely ill and convalescent elderly patients.
The pharmacokinetics of ciprofloxacin were evaluated in 13 elderly patients with serious infections who were receiving 750 mg orally every 12 hours. The acute evaluations were performed within 24 hours of admission (n = 13), whereas the convalescent evaluations were performed at the end of therapy (n = 7). Serum and urine concentrations of ciprofloxacin were measured using high-performance liquid chromatography. Peak serum concentration (Cmax), terminal elimination half-life (t1/2 beta), apparent total body clearance (CL/f), and apparent volume of distribution (Vd/f) of ciprofloxacin were 5.97 +/- 2.95 mg/liter, 5.31 +/- 2.00 hours, 8.12 +/- 3.83 ml/kg/minute, and 3.63 +/- 1.91 liters/kg during the period of acute illness. Cmax and Vd/f values were moderately increased during the convalescent phase (8.56 +/- 3.43 mg/liter versus 5.87 +/- 2.25 mg/liter, p = 0.138, and 5.95 +/- 3.23 liters/kg versus 3.46 +/- 1.40 liters/kg, 0.05 less than p less than 0.1). The CL/f and t1/2 beta (four to 12 hours) values, however, were not significantly altered. The observed pharmacokinetic characteristics, which are consistent with those derived from single-dose studies in healthy elderly subjects, are markedly different from previous observations in young adult volunteers. However, acute illness does not alter the pharmacokinetics of ciprofloxacin in the elderly. Dosage alterations because of the presence of acute illness in the elderly do not appear to be warranted.
Administration, Oral↗
Gentamicin disposition in young and elderly patients with various degrees of renal function.
The effect of aging on the total body clearance, volume of distribution, and half-life of gentamicin was examined in 99 febrile patients with various degrees of renal function. In the 50 patients who were 18 to 64 years old, clearance of gentamicin was 79.0 +/- 27.0 mL/min (mean +/- standard deviation), creatinine clearance was 98.6 +/- 33.3 mL/min, volume of distribution was 0.242 +/- 0.077 L/kg, and half-life was 2.63 +/- 0.90 hours. In the 49 patients who were 65 to 90 years old, these values were 36.9 +/- 16.3 mL/min, 51.2 +/- 21.2 mL/min, 0.244 +/- 0.102 L/kg, and 5.80 +/- 4.13 hours. Significant differences were observed between the two groups for all parameters except volume of distribution. Linear regression revealed good correlations between the disposition characteristics (clearance and elimination-rate constant) of gentamicin and age as well as creatinine clearance. However, there was no apparent relationship between the ratio of gentamicin clearance to creatinine clearance and age (r = .0731). These findings suggest that the disposition of gentamicin is independent of age but dependent on renal function.
Adult↗
Disposition of famotidine in renal insufficiency.
The disposition of famotidine was evaluated in 18 patients; Group 1, mild renal insufficiency, [creatinine clearance (CLCR): 30-60 mL/min]; Group 2, moderate to severe renal insufficiency (CLCR: 10-30 mL/min); Group 3, end-stage renal disease requiring maintenance hemodialysis (anuric). Blood and urine samples were obtained over a 72-hour period. Plasma concentration-time data demonstrated biexponential decay. The terminal elimination half-life was prolonged in Group 3 (18.6 +/- 5.7 hr) compared with Groups 1 (9.3 +/- 2.3 hr) and 2 (9.7 +/- 1.7 hr), P less than .05. Steady-state volume of distribution ranged from 0.80 to 1.26 L/kg but did not differ among the groups. Total body clearance (CLp) and renal clearance were significantly lower in Groups 2 and 3 patients compared with Group 1 patients. Nonrenal clearance was not related to CLCR. The CLp correlated well with CLCR (CLp = 1.59 CLCR + 33.8, r = 0.830, P less than .05). These data indicate that dosage adjustment may be necessary in patients who have renal insufficiency.
Adult↗
Bioavailability and disposition of metoclopramide after single- and multiple-dose administration in diabetic patients with gastroparesis.
The disposition of metoclopramide after acute and chronic administration was determined in four diabetic patients with gastroparesis who had a creatinine clearance of 70.8 +/- 10.7 mL/min (mean +/- SD). Single, 10-mg oral and intravenous doses were administered on days 1 and 2, respectively, followed by 10 mg orally every six hours for three weeks. A second, 10-mg intravenous bolus dose was administered on the last morning of chronic therapy. Metoclopramide concentrations were determined by high performance liquid chromatography. The elimination half-life, steady-state volume of distribution, and total body clearance after the initial intravenous dose were 3.9 +/- 1.2 hr, 2.7 +/- 0.3 L/kg, and 0.57 +/- 0.14 L/hr/kg, respectively. The initial bioavailability was 67.7 +/- 12.6%. After three weeks of chronic therapy, no significant differences in total body clearance (0.72 +/- 0.42 L/hr/kg) or bioavailability (77.5 +/- 16.8%) were observed. Thus the pharmacokinetics and bioavailability of metoclopramide were not altered during chronic therapy in these diabetic patients.
Adult↗
Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers.
The pharmacokinetics of codeine, codeine glucuronide, morphine, and morphine glucuronide were assessed after single- (60 mg) and multiple-dose (60 mg every six hours for nine doses) oral administration of codeine sulfate to six normal volunteers. Multiple blood and urine samples were collected after administration of the single- and last multiple-oral doses. Drug concentrations were analyzed using radioimmunoassay techniques. No significant alterations in codeine pharmacokinetics were noted after multiple-dose oral administration. However, accumulation of morphine during multiple dosing was significant (AUC24 = 102 +/- 33 ng/mL/hr after single dose versus 212 +/- 118 ng/mL/hr after the last multiple dose). Peak concentration and AUC24 data for morphine glucuronide indicated that significant accumulation of this compound occurs upon multiple-dose administration. These data indicate that morphine and morphine glucuronide serum concentrations are significantly increased during chronic oral codeine therapy and suggest that morphine, and perhaps morphine glucuronide, contribute significantly to the analgesic activity of chronic oral codeine therapy.
Adult↗
Systemic absorption of oral vancomycin in patients with renal insufficiency and antibiotic-associated colitis.
The systemic absorption of orally administered vancomycin was evaluated in five patients (six occasions) with moderate to severe renal insufficiency and documented antibiotic-associated colitis. The patients' ages ranged from 28 to 63 years and weights varied from 50.0 to 76.2 kg. Vancomycin doses were 125 mg (one case), 250 mg (three cases), and 500 mg (two cases) every six hours. Multiple serum concentrations were obtained (range four to 19) during the seven- to 28-day courses of vancomycin therapy. Vancomycin serum concentrations were detectable in five of the six cases as soon as two hours after the first dose, and plateaued within four days. A linear relationship between daily dose and the vancomycin serum concentration was observed (r = .8575, P less than .01). Routine monitoring of vancomycin serum concentrations in adult patients may not be necessary unless high dose (greater than 2 g/d) or prolonged therapy (greater than ten days) is required.
Administration, Oral↗
Influence of gender on the disposition of cefotaxime and desacetylcefotaxime.
The pharmacokinetics of cefotaxime and desacetylcefotaxime were evaluated in 11 female and 13 male subjects with end-stage renal disease. Subjects received single 1- or 2-g intravenous doses of cefotaxime sodium. Serum, urine, and dialysate concentrations of cefotaxime and desacetylcefotaxime were determined using high performance liquid chromatography. The results indicate that gender has no clinically significant influence on the disposition of cefotaxime or its active metabolite desacetylcefotaxime.
Cefotaxime↗
The effect of famotidine on renal function in patients with renal insufficiency.
The effect of famotidine, a new histamine H2-receptor antagonist, on renal tubular creatinine secretion was evaluated in twelve patients with reduced renal function (creatinine clearance 10-60 ml min-1). Creatinine and inulin clearances were determined at baseline and for 4 h after a 10 mg intravenous dose of famotidine. Famotidine renal clearance exceeded inulin clearance by an average of 152%, indicating that renal tubular secretion of famotidine occurred. No significant changes in the clearances of creatinine or inulin, or the fractional clearance of creatinine were observed after famotidine administration. These data suggest that famotidine, unlike cimetidine, does not inhibit renal tubular secretion of creatinine. Thus, famotidine does not affect creatinine-dependent measurements of renal function and is unlikely to alter the renal elimination of basic drugs.
Adult↗
Effects of renal insufficiency on the pharmacokinetics and pharmacodynamics of opioid analgesics.
The disposition and pharmacologic activities of morphine, meperidine, methadone, propoxyphene, dihydrocodeine, and codeine are reviewed. Dose-related toxicities of these opioid analgesics include mental obtundation, respiratory depression, and hypotension. Furthermore, convulsions have been associated with normeperidine and cardiac toxicities with norpropoxyphene. Hepatic metabolism is the primary route of elimination, except for methadone, for which there is also significant renal excretion. Although the pharmacokinetics of morphine are unchanged in renal insufficiency, accumulation of active metabolites may lead to narcosis. Similar accumulation of normeperidine and norpropoxyphene, metabolites of meperidine and propoxyphene, respectively, as well as propoxyphene itself, and dihydrocodeine and codeine may explain reports of adverse reactions in patients with impaired renal function. A high index of suspicion of opioid-induced toxicities should be maintained in patients who have renal dysfunction and receive opioids.
Humans↗
Pharmacokinetics of cetirizine in the elderly and patients with renal insufficiency.
The disposition of cetirizine, a new H1-receptor antagonist, was evaluated in 30 healthy adults of various ages and in 15 adults with various degrees of renal insufficiency. The purpose of the evaluation was to determine whether dosage schedules of cetirizine will require modification in the elderly or patients with renal insufficiency. We found that the elimination half-life of cetirizine was prolonged in patients with mild and moderate renal insufficiency, compared with age-matched individuals with normal renal function (19.0 +/- 3.3 and 20.9 +/- 4.4 hours, vs 7.4 +/- 3.0 hours, respectively). However, the mean apparent steady-state volume of distribution did not differ significantly between these subject groups (range 0.41 to 0.47 L/kg). Total body clearance and renal clearance of the drug were both significantly lower in the patients with renal insufficiency. In elderly subjects, the elimination half-life of cetirizine was significantly prolonged compared with younger adults, and apparent total body clearance was significantly reduced. Again, there was no significant difference in the volume of distribution between the groups. Linear regression showed good correlations between the disposition characteristics of cetirizine and age as well as creatinine clearance. However, we found no relationship between age and the ratio of apparent total body clearance of cetirizine to creatinine clearance. Thus the disposition of cetirizine is independent of age but dependent on renal function. The relationship between apparent total body clearance of cetirizine and creatinine clearance was significant only in patients with creatinine clearances greater than 40 mL/min. Progressive decrements in creatinine clearance were not associated with similar changes in the pharmacokinetic parameters of cetirizine.
Adult↗