Chlordiazepoxide and oxazepam disposition in cirrhosis.

When disease impairs clearance of drugs, multiple-dose therapy may result in cumulation. The disposition of chlordiazepoxide (CDX), 50 mg infused intravenously over 10 min, was studied in 14 normal subjects and in 11 patients with biopsy-proven cirrhosis. In the normal subjects, mean (+/- SE) kinetic parameters were: t 1/2 beta, 10.0 (+/- 0.9) hr; Vd, 0.38 (+/- 0.04) l/kg; clearance, 0.54 (+/- 0.13) ml/min/kg. Clearance of total drug correlated inversely with serum albumin concentration in normal subjects (r = -0.63). Values in cirrhotic patients were: t 1/2 beta, 34.9 (+/- 8.7) hr; Vd, 0.34 (+/- 0.024) 1/kg; and clearance, 0.185 (+/- 0.34) ml/min/kg. Desmethylchlordiazepoxide (DMCDX), the major metabolite of CDX, appeared in blood of cirrhotic patients less rapidly than in normal subjects. Severity of liver disease did not indicate the impairment of CDX clearance. In 5 of the same cirrhotic patients, mean t 1/2 beta for oxazepam (7.1 +/- 1.0 hr) was 27% longer than in control subjects (5.6 +/- 0.7 hr); the difference is not significant. On kinetic grounds oxazepam may be preferable to chlordiazepoxide in cirrhotic patients since its elimination kinetics are not greatly altered in cirrhosis.     

Lorazepam kinetics in the elderly.

Lorazepam is a 3-hydroxy-1,4-benzodiazepine derivative biotransformed by glucuronide conjugation, followed by urinary excretion of the glucuronide metabolite. The kinetic properties of single 1.5- to 3.0-mg doses of intravenous lorazepam were assessed in 15 healthy elderly subjects, 60 to 84 yr of age, and in 15 healthy young subjects, 19 to 38 yr of age. Volumes of distribution for lorazepam in the elderly group (mean, 0.99 1/kg), were slightly but significantly smaller than in the young group (1.11 1/kg), suggesting less extensive drug distribution in the elderly. Values of elimination half-life (t1/2beta) in the elderly (15.9 hr) did not differ significantly from those in the young group (14.1 hr), but total clearance in the elderly (0.77 ml/min/kg) was 22% less (p less than 0.05) than in the young subjects (0.99 ml/min/kg). Age differences in lorazepam clearance were partly explained by more frequent cigarette smoking in the young subjects. Gender had no apparent relationship to kinetics. The rate and completeness of absorption of intramuscular (IM) and oral loraxepam was assessed in 10 of the elderly subjects. Deltoid IM injection and oral administration of tablets in the fasting state led to rapid absorption of lorazepam into the systemic circulation. Peak plasma lorazepam concentrations were always reached within 2.5 hr, and values of absorption half-life (t1/2a) did not exceed 45 min. Absorption of IM and oral lorazepam was 80% to 100% complete. Thus, the aging process is associated with small changes in the kinetics of lorazepam. IM and oral administration of lorazepam in elderly persons, as in the case of young individuals, leads to rapid and nearly complete absorption into the systemic circulation.     

Observations on the pharmacokinetics of acebutolol.

Using a balance, randomized, crossover design, single intravenous (1 mg/kg) or oral (3 X 100 mg) doses of acebutolol were administered at weekly intervals to 6 healthy volunteers. For each subject venous blood samples and timed urine collections were obtained after each treatment. Plasma and urinary acebutolol levels were measured by a spectrophotometric method that measures acebutolol and its N-acetyl metabolite (which has equivalent cardiac activity). Using a computer program, various pharmacokinetic parameters were estimated from the date of each subject. From the intravenous data (obtained up to 6 hr after dosing), the following mean (+/-SD) values were found: distribution half-life (T 1/2D), 0.60 (+/-0.43) hr, plasma elimination half-life (T 1/2El), 3.2 (+/-1.1) hr, apparent volume of distribution (VD), 224 (+/-69) L, and apparent VD/kg, 3.0 (+/-0.8) L/kg. Using the oral data (obtained up to 10 hr after dosing), the value for T 1/2El was 3.2 (+/-0.9) hr. The mean cumulative urinary recovery (expressed as % dose) after the intravenous route was about 60%, while that after the oral route was of the order of 35%, suggesting that about half of the oral dose reached the systemic circulation. The mean creatinine clearance of the 6 subjects was 103 (+/-7) ml/min, while the value (obtained between 2 and 4 hr after intravenous dosing) for renal clearance of acebutolol as measured was 298 (+/-68) ml/min and the corresponding plasma clearance was 818 (+/-64) ml/min. These results support the occurrence of substantial nonrenal elimination and renal tubular secretion.     

Ranitidine does not impair oxidative or conjugative metabolism: noninteraction with antipyrine, diazepam, and lorazepam

Potential interactions of ranitidine with antipyrine, diazepam, and lorazepam were evaluated. Ten healthy male subjects were injected intravenously with antipyrine (1.2 gm), diazepam (10 mg), or lorazepam (2 mg) on two randomly assigned occasions, once in the otherwise drug-free state and once while concurrently taking a therapeutic ranitidine dose of 150 mg every 12 hr. Kinetic analysis for antipyrine showed no change in elimination t1/2 between trials (mean, 11.6 and 11.5 hr) with no change in volume of distribution (Vd) or total clearance (0.77 and 0.75 ml/min/kg). Diazepam analysis also showed unchanged t1/2 (32.3 and 28.9 hr) with no change in Vd or total clearance (0.42 and 0.39 ml/min/kg). Lorazepam as well had unchanged t1/2 (11.7 and 11.3 hr), Vd, and total clearance (1.52 and 1.65 ml/min/kg). Therefore ranitidine, unlike cimetidine, has no effect on either human hepatic drug oxidation, as measured by antipyrine and diazepam clearance, or human drug conjugation, as measured by lorazepam clearance.     

Lorazepam and oxazepam kinetics in women on low-dose oral contraceptives

Women on low-dose estrogen oral contraceptives (OC) and drug-free control women matched for age, weight, and cigarette smoking habits, received single 2-mg IV doses of lorazepam or single 30-mg oral doses of oxazepam, two benzodiazepines metabolized by glucuronide conjugation. Kinetics were determined from multiple plasma concentrations measured during 48 hr after dosing. Mean kinetic variables for lorazepam in control and OC groups (n = 15 in each group) were: volume of distribution (Vd), 1.33 and 1.45 l/kg; elimination t1/2, 13.1 and 12.2 hr; total clearance, 1.25 and 1.50 ml/min/kg; free fraction in plasma, 10.3% and 10.3% unbound. For oxazepam, kinetic variables in the two groups (n = 14 and 17) were: Vd, 1.05 and 1.19 l/kg; t1/2, 7.6 and 7.2 hr; total clearance, 1.60 and 2.03 ml/min/kg; free fraction, 4.6% and 4.9% unbound. None of these differences were significant. Thus, metabolic clearance by glucuronidation of lorazepam and oxazepam is not significantly affected by OC, in contrast with the highly significant reduction in clearance of the oxidized benzodiazepine diazepam.     

Moxalactam kinetics in hemodialysis

In eight patients with end-stage renal disease undergoing chronic hemodialysis moxalactam kinetics were examined. Volume of distribution (Vd), dialysance (Cd), and serum half-life (t1/2) were determined during dialysis with a 1.3 or 1.6 m2 dialyzer. The t1/2 was also determined during the interdialytic period. Vd was 0.25 +/- 0.04 l/kg and Cd was 32.6 +/- 11.7 ml/min and 67 +/- 25.5 ml/min with the 1.3 and 1.6 m2 dialyzers. The t1/2 was 4.8 +/- 0.9 hr using the 1.3 m2 dialyzer and 2.8 +/- 0.6 hr using the 1.6 m2 dialyzer. Moxalactam t1/2 during the interdialytic period was 23.4 +/- 9.6 hr.     

PERFORMANCE OF TWO PREDICTIVE METHODS FOR CALCULATION OF THE KEY PHARMACOKINETIC PARAMETERS FOR GENTAMICIN DOSAGE INDIVIDUALIZATION

Performance of two methods for determination of the apparent volume of distribution (Vd) and the elimination half-life (t1/2) for gentamicin was evaluated in 20 non-obese acutely ill patients. The patients had varying degrees of renal function. Initial creatinine clearance ranged from 22.7-103.1 ml/min, with a mean value (+/- SEM) of 63.26 (+/- 5.74) ml/min, and serum creatinine concentration was 1.37 (+/- 0.13) mg/dl, with a range of 0.70-3.0 mg/dl. The total daily dose of gentamicin ranged from 1.85-4.71 mg/kg. Two different methods were used for Vd calculation: the Hull-Sarubbi method and Chiou midpoint-back-extrapolation method. For t1/2 estimation, the Hull-Sarubbi and Cutler methods were used. These values were compared with the values obtained by the Sawchuk-Zaske method. Mean predicted error (ME), mean absolute error (MAE), and root mean squared error (RMSE) were calculated for each method. Prediction bias and precision were compared statistically between each method by calculating the 95% confidence intervals of the delta MA and delta MAE, respectively. The MAEs revealed that the precision of Vd predictions were within 1.04 litre and 0.62 litre for the Hull-Sarubbi and Chiou methods, respectively. For the elimination half-life, none of the methods performance exhibited substantial bias. The Hull-Sarubbi method, however, was less biased and more precise than the Cutler method.     

Kinetics of fenoximone, a new cardiotonic, in healthy subjects

Fenoximone, a new cardiotonic, was given to six healthy men as a single intravenous dose of 1 mg/kg and a single oral dose of 3 mg/kg as solution in a crossover study. Plasma concentrations were monitored for 8 hr and urine was collected for 24 hr. Peak plasma concentrations (Cmax) were reached 30 min after the oral dose. Decay of plasma concentrations was fitted to a mean (+/- SD) elimination t1/2 (t1/2 beta) of 60 +/- 14 min after intravenous injection and 78 +/- 26 min after oral dosing. Mean total body clearance for intravenous dosing was 2062 +/- 846 ml/min, renal clearance (ClR) was 5.3 +/- 2.4 ml/min, and extrapolated volume of distribution was 0.37 +/- 0.26 l/kg. The sulfoxide derivative was detected as the main metabolite. Cmax of the sulfoxide metabolite occurred 10 min after the end of the intravenous infusion and 20 to 60 min after oral dosing. From the decay of the plasma concentrations of the sulfoxide, the t1/2 beta s were calculated as 132 +/- 15 min after intravenous injection and 140 +/- 27 min after oral dosing of fenoximone. ClR of the sulfoxide was 499 +/- 106 ml/min after intravenous injection; 24-hr urinary recovery of the sulfoxide was 75.7% +/- 5.7% after intravenous injection and 64.3% +/- 10.4% after oral dosing. Mean oral bioavailability of fenoximone was 53% (range 44% to 69%).     

Age and cibenzoline disposition

Oral cibenzoline kinetics were followed in 36 healthy subjects aged from 22 to 78 yr divided into groups of six subjects per decade between 20 and 80 yr. Each received a single, oral, 160-mg dose of cibenzoline. Blood and urine samples were collected for 72 hr. Cibenzoline plasma and urine concentrations were measured by HPLC. Maximum plasma cibenzoline concentrations (Cmax) ranged from 283 to 1100 ng/ml and occurred 1 to 2.5 hr after dosing. Apparent oral clearance (ClT) ranged from 401 to 1677 ml/min and the t 1/2 ranged from 5.9 to 13.4 hr. Nonrenal clearance (ClNR) ranged from 65 to 1113 ml/min, renal clearance (ClR) ranged from 165 to 645 ml/min, and 31% to 86% of the dose was recovered unchanged in urine (Xu). The volume of distribution (Vd) was large, ranging from 236 to 948 l. There was a significant relationship between age and the following kinetic parameters: Cmax, Xu, t 1/2 (all of which increased with age), ClT, ClR, ClNR, the terminal elimination rate constant beta, and Vd (which decreased with age). Mean ClT was 999 +/- 371 ml/min in the 20- to 30-yr age group and was 465 +/- 78 ml/min in the 70- to 80-yr age group. The change in ClT with age resulted from a decreased in both ClR and ClNR. Mean t 1/2 varied from 7 hr in the youngest group to 10.5 hr in the oldest group. The age-related changes in cibenzoline kinetics occurred over the entire age range studied and the relationship between age and these kinetic parameters appeared to be linear.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of chlordiazepoxide: sex differences and effects of oral contraceptives.

There is considerable interspecies and interdrug variability in the effect of sex differences and oral contraceptive (OC) steroids on hepatic drug elimination. Their influence on the disposition of chlordiazepoxide has been studied in 11 healthy young men (29 +/- 5 yr), 11 healthy young women (28 +/- 5 yr), and 7 healthy women receiving OC steroids (27 +/- 2 yr) for more than 6 months. The elimination half-life (t1/2(beta)) was longer (from 14.8 +/- 5.9 hr to 8.9 +/- 2.5 hr) and protein binding less (95.5 +/- 1.4% and 97.0 +/- 1.2%) in women than in men. Weight-normalized plasma clearances of total drug did not differ, but the clearance of unbound drug was significantly less in women (8.7 +/- 5.0 ml/min/kg) than in men (15.6 +/- 5.3 ml/min/kg). Women on OC steroids had a lower plasma binding (from 93.6 +/- 1.5% to 95.5 +/- 1.4%) and a higher volume of distribution (from 0.62 +-/ 0.23 l/kg to 0.40 +/- 0.14 l/kg) than women not on OC steroids. The elimination t1/2 was longer (from 24.3 +/- 12 hr to 14.8 +/- 5.9 hr) and the clearance of unbound drug lower (from 5.7 +/- 3.0 ml/min/kg to 8.7 +/- 5.0 ml/min/kg) in women on OC steroids than in those not using them, but these differences were not statistically significant.     

Single- and multiple-dose metronidazole kinetics

Kinetics of metronidazole and its metabolites were examined after single oral and intravenous doses and multiple oral doses in seven subjects by a sensitive HPLC assay. After 400 mg metronidazole IV, mean Vd beta was 1.05 l/kg. Mean plasma t1/2 was 8.3 hr with a ClTBC of 1.31 ml/min/kg. Clearance to the major metabolites, 2-hydroxy-metronidazole and 1-acetic acid metronidazole, accounted for over 90% of the ClTBC. After a single oral 400-mg metronidazole dose, the development of peak metronidazole plasma concentrations of 6.9 micrograms/ml averaged 2.3 hr after dosing. Systemic oral bioavailability was complete (98.9%). During twice-daily multiple metronidazole dosing, 400 mg, metronidazole kinetics were the same. Elimination t1/2 was 8.3 hr and average predicted steady-state metronidazole concentrations during one dosing interval (6.3 +/- 0.5 micrograms/ml; mean +/- SE) were equal to the observed concentrations (6.9 +/- 1 micrograms/ml). Urinary excretion of unchanged metronidazole was below 10% of the total dose. Seventy-five percent of the dose was 2-hydroxy-metronidazole and 1-acetic acid metronidazole, and 15% was conjugates of metronidazole and 2-hydroxy-metronidazole.     

Imipenem pharmacokinetics in patients with burns

The pharmacokinetics of imipenem were studied in 11 adult patients with severe burns who were receiving a therapeutic regimen of imipenem-cilastatin 500 mg intravenously every 6 hours. Serial blood samples for measuring imipenem and 24-hour urine collections for creatinine clearance (CrCl) were obtained after the initial dose and after multiple dosing. Plasma was assayed for imipenem by use of HPLC. A two-compartment model provided a superior fit to the data compared with a one-compartment model in 9 of the 11 patients. There was no significant difference in any pharmacokinetic parameter between the initial dose and after multiple dosing (p greater than 0.05). Combined mean (+/- SD) parameter estimates for the two dosing periods were as follows: VC, 0.11 +/- 0.06 L/kg; Vss, 0.22 +/- 0.06 L/kg; CL, 12.5 +/- 3.6 L/hr/1.73 m2; t1/2 alpha, 0.18 +/- 0.13 hr; t1/2 beta, 1.12 +/- 0.44 hr. Mean clearance in two patients with creatinine clearance values greater than 150 ml/min/1.73 m2 was 17.7 L/hr/1.73 m2. Mean clearance in two patients with creatinine clearance values less than 50 ml/min/1.73 m2 was 8.5 L/hr/1.73 m2. No pharmacokinetic parameter was significantly different from previously reported parameters in normal volunteers (p greater than 0.05). Creatinine clearance ranged from 17 to 218 ml/min/1.73 m2. Imipenem clearance was significantly related to creatinine clearance (CL = 63 + 0.059 CLCR; r2 = 0.60, p = 0.001). No significant association was found between total body surface area burns and imipenem clearance (p greater than 0.05). Our data suggest imipenem pharmacokinetics in patients with burns are comparable to those in normal volunteers although substantial intersubject variability exists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clovoxamine kinetics in an early clinical trial

Elimination kinetics of the new antidepressant clovoxamine were determined in a preliminary clinical trial in 10 depressed patients. When final oral doses of 50 mg clovoxamine fumarate were given, the mean peak steady-state plasma concentration was about 60 ng/ml after 3 hr. Clovoxamine elimination proceeded by an apparent single-phasic, first-order decline with a mean t1/2 of 9.5 +/- 2.8 hr. One subject had an unusually long t1/2 (31.5 hr) and had correspondingly high clovoxamine plasma concentrations. The mean apparent volume of distribution (Vd) calculated from oral dosage was 19.5 +/- 6 l/kg, but one atypical subject had an apparent Vd of 96 l/kg. The mean apparent oral clearance was 25.5 +/- 12.5 ml/min/kg. These parameters should be of assistance in planning dosage regimens and monitoring therapeutic blood levels according to kinetic principles. Atypical clovoxamine kinetics can be associated with abnormally high or low blood levels and could therefore lead to variability in clinical response.     

Amiodarone pharmacokinetics. III. Influence of thyroid dysfunction on amiodarone absorption and disposition

Hypothyroid, hyperthyroid and euthyroid rats were given 45 or 80 mg/kg i.v. or 100 mg/kg p.o. of amiodarone hydrochloride to determine the effects of thyroid dysfunction on the absorption and disposition characteristics of amiodarone. Serial blood samples were obtained for 48 hr and assayed for amiodarone and desethylamiodarone by high-performance liquid chromatography. In the hypothyroid rats, reductions in amiodarone clearance (CL) of 73% (26.9-7.3 ml/min/kg) and 61% (18.7-7.3 ml/min/kg) were observed with the 45- and 80-mg/kg i.v. bolus doses, respectively. Accompanying the decreases in CL were increases in the terminal disposition half-life (T1/2 gamma), 89% (18-34 hr) with the 45-mg/kg dose and 185% (20-57 hr) after the 80-mg/kg dose. The steady state (Vss) and apparent (Vd) volumes of distribution were smaller at the lower dose but were invariant after administration of the larger dose. Furthermore, the central compartment volume was not altered. In the hyperthyroid rats, a 67% increase in CL (12.8-21.4 ml/min/kg) and 75 to 80% increases in Vss (15.5-27.1 liters/kg) and Vd (25.0-44.8 liters/kg) were observed with the 45-mg/kg of amiodarone dose. However, no changes in CL, Vd and Vss were seen with the 80-mg/kg dose. Furthermore, gamma, T1/2 gamma and central compartment volume were not altered in the hyperthyroid rats. The effects of thyroid dysfunction on the p.o. bioavailability characteristics of amiodarone were minor. These studies demonstrated that the disposition kinetics of amiodarone are altered in hypo- and hyperthyroidism.     

Disposition kinetics of quinidine.

The disposition kinetics of quinidine in 12 hospitalized patients in whom oral quinidine therapy was to be initiated is described. Quinidine in doses of 2.6 to 5.2 mg/kg base were infused intravenously over 22 min. Plasma samples were collected during the postinfusion for 24 hr and analyzed by a specific and sensitive assay procedure. In the 12 hr after administration, postinfusion plasma quinidine concentration decay was described by a biexponential equation. Attempts to include the 24-hr data point in the fitting procedures resulted in poorer agreements between the theoretical and experimental curves. A 2-compartment open model is proposed to describe the disposition of quinidine. The volume of the central pool (Vc) and steady-state volume of distribution (Vdss) were 0.91 +/- 0.11 L/kg and 3.03 +/- 0.25 L/kg, respectively, and indicate that quinidine distribution is predominantly extravascular. Quinidine distribution was quite rapid (t1/2alpha = 7.19 +/- 0.70 min), while the apparent elimination half-life (t1/2beta) was considerably longer, 6.333 +/- 0.47 hr. Total body plasma clearance ranged from 1.49 to 7.15 ml/min/kg (mean 4.70) and is primarily associated with nonrenal mechanisms of drug elimination. Urine specimens collected for 48 hr indicated that 17% of the dose is excreted intact and that urinary excretion was essentially complete within 24 hr. Renal clearance (Clr) was 0.80 +/- 0.18 ml/min/kg. The study demonstrated that there is substantial interpatient variability with respect to quinidine disposition.     

Kinetics of high-dose intravenous morphine in cardiac surgery patients.

Ten patients received 1.0 mg/kg of morphine sulfate by constant-rate intravenous infusion at 5 mg/min over 9 to 27 min. Multiple arterial blood samples were drawn during the first 30 to 151 min after termination of the infusion, prior to institution of cardiopulmonary bypass. Postinfusion plasma concentrations were fitted by computer to biexponential functions consistent with a 2-compartment open pharmacokinetic model. Mean (+/- SE) pharmacokinetic parameters were: volume of central compartment, 0.09 +/- 0.03 L/kg; total apparent volume of distribution, 1.02 +/- 0.09 L/kg; distribution T 1/2, 0.90 +/- 0.09 min; apparent elimination T 1/2, 137 +/- 14 min; total clearance, 378 +/- 63 ml/min. Thus distribution of morphine is very rapid, but the apparent volume of distribution is only slightly larger than body weight, suggesting limited tissue uptake. Since apparent elimination T 1/2s are similar to those reported after smaller doses, evidence of saturable or capacity-linked elimination is lacking. Total clearances, representing mainly hepatic clearance, averaged about 25% of hepatic blood flow, suggesting clinically important first-pass metabolism of oral morphine.     

Disposition of diazepam and its major metabolite desmethyldiazepam in patients with liver disease.

In six patients with cirrhosis and five patients with fibrosis of the liver elimination of diazepam (D) was compared after single and subchronic dosage. The pharmacokinetics of the major metabolite desmethyldiazepam (DD) was investigated in four healthy individuals and four patients with hepatic dysfunction and compared to its parent compound D. In the initial study, 11 patients with liver disease (cirrhosis and fibrosis) had a longer half-life (T 1/2(beta) of 99.2 +/- 23.2 hr after a single intravenous bolus of 0.1 mg/kg of D than to age-matched normal subjects (46.6 +/- 14.2). After subchronic treatment with 10 mg of D for 7 days T 1/2(beta) was prolonged only slightly (p = 0.043) in these patients (107.6 +/- 25.2 hr). Neither total plasma clearance (Cl) nor the apparent volume of distribution (VdSS or VdCl) showed significant changes. After intravenous injection of DD (0.1 mg/kg) plasma levels declined in the same biexponential manner as after D. The cross-over study in the four normal subjects demonstrated that DD was eliminated much more slowly than D. Whereas for D, T 1/2(beta) and Cl were 32.6 +/- 11.3 hr and 32.3 +/- 11.0 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min, respectively, the corresponding values for DD were 50.9 +/- 6.2 hr and 11.3 +/- 3.1 ml/min. The accumulation of DD after multiple dosage could be explained by the fact that it is formed faster from D than it is eliminated. In four patients with liver disease the elimination of D and the elimination of DD were altered. In these patients T 1/2(beta) for DD was prolonged (p = 0.015) to 108.2 +/- 40.3 hr. This prolongation was caused by a decrease in Cl of 4.6 +/- 1.1 ml/min, (p = 0.003) whereas Vd(Cl) did not change significantly. This indicates that at least two steps in diazepam metabolism are impaired in patients with liver disease.     

Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis

Pharmacokinetics of zidovudine (azidothymidine, AZT) was investigated after oral administration (200 mg) in 25 HIV seronegative subjects: 14 patients with severe renal impairment (creatinine clearance 6 to 31 ml/min), five hemodialyzed anuric patients, and six healthy subjects. Plasma and urine concentrations of zidovudine and its glucuronidated metabolite (GAZT) were measured simultaneously by HPLC assay. In healthy subjects, GAZT concentrations were higher than those of AZT; AUC values were 23.7 +/- 1.9 and 5.2 +/- 0.6 mumol.hr/L, respectively. Formation of GAZT rate-limits its elimination: GAZT half-life (t 1/2) parallels that of AZT, which is around 1 hour. In uremic patients, AZT concentrations were moderately increased (AUC = 11.7 +/- 1.1 mumol.hr/L), whereas t 1/2 and mean residence time (MRT) remain unchanged despite the decreased renal clearance (16 +/- 2 versus 220 +/- 58 ml/min) and decreased urinary excretion (1.6 +/- 0.3 versus 8.1 +/- 1.0% of the dose). In contrast, GAZT concentrations are markedly increased (AUC = 402.9 +/- 88.6 mumol.hr/L). As a consequence of the decreased renal clearance (27 +/- 3 versus 331 +/- 42 ml/min), elimination is the rate-limiting step and t 1/2 is increased (8 +/- 2 versus 0.9 +/- 0.1 hr). Contribution of a 4-hour hemodialysis session to AZT elimination appears to be negligible, whereas elimination of GAZT is enhanced. On the sole basis of AZT pharmacokinetic data, no particular dose adjustment appears to be necessary in patients who have severe renal impairment (creatinine clearance between 10 and 30 ml/min). However, high levels of GAZT should be anticipated with the usual dosage regimen.     

Cotinine disposition and effects

Cotinine is the major metabolite of nicotine in man. We studied cotinine disposition kinetics in 28 healthy habitual cigarette smokers. Eight subjects received cotinine fumarate, 4 micrograms base/kg/min IV for 60 min. Mean (+/- SD) metabolic clearance was 60 +/- 12 ml/min and mean renal clearance was 12 +/- 5 ml/min, averaging 17% of total clearance. Steady-state volume of distribution was slightly greater than body weight (mean 88 +/- 17 l). Terminal t 1/2 averaged 15.8 +/- 4.0 hr in these eight subjects and 19.7 +/- 6.5 hr in another 12 subjects who abstained from smoking for 3 days. The effect of urinary acidification and alkalinization on renal clearance of cotinine during cigarette smoking was studied in another group of eight subjects. Compared with baseline (mean urinary pH 5.8, renal clearance 12.3 +/- 5.9 ml/min), renal clearance was increased about 50% by urinary acidification (pH 4.4, clearance 18.6 +/- 10 ml/min), but it was not affected by alkalinization (pH 6.7, clearance 14.0 +/- 10.4 ml/min). Infusion of cotinine to blood concentrations seen in moderately heavy smokers had no effect on heart rate, blood pressure, or skin temperature, measures that are sensitive to effects of nicotine. No spontaneous subjective effects were reported. We conclude that, at levels to which cigarette smokers are generally exposed, cotinine exerts no cardiovascular activity and weak, if any, psychologic activity.     

Difference in trimethoprim pharmacokinetics between children and adults

We used a new micromethod, an application of a previously published high-performance liquid chromatography assay, to investigate trimethoprim (TMP) pharmacokinetics in children. The subjects were 5 girls who were treated for urinary tract infection with a TMP suspension, 6 mg/kg/day, twice daily for 10 days. Elimination studies were done after the last dose. The girls were 1.08-9.71 years old. 3 healthy adult males, aged 26.35-37.31 served as controls. The half-life (t 1/2) of TMP in the children was 3.0-5.5 versus 9.3-13.6 h in the adults. The volume of distribution (Vd) was 0.7-1.1 1/kg in the children and 0.5-0.9 1/kg in the adults. Plasma clearance (Clp) was 2.1-2.8 ml/min/kg for the children. The adults had a smaller Clp of 0.4-1.2 ml/min/kg. From this and previous studies we conclude that the t 1/2 of TMP is much shorter in children than in adults.