Protein binding of glycopeptide antibiotics with diverse physical-chemical properties in mouse,rat, and human serum

In previous studies of the pharmacokinetics and urinary excretion of nine glycopeptides with diverse isoelectric points (pI),as pIdecreases, the total systemic and renal clearance, urinary recovery, and volume of distribution decrease, whereas the half-life increases. With glycopeptides of similar pI,clearance decreases and half-life increases with increasing lipophilicity. The present study examines the serum protein binding of these glycopeptide antibiotics in mouse, rat, and human serum and calculates the previously reported pharmacokinetic parameters for these drugs based on unbound concentration. Increased negative charge and lipophilicity increase serum protein binding (90-fold, f_u 83% to 0.96%), which decreases the renal clearance and total systemic clearance (90-fold, 16.4 to 0.18 ml/min/kg) of these drugs. Increased serum protein binding also decreases the volume of distribution of these compounds, but this change is relatively small (sixfold, 755 to 131 ml/kg) compared with the change in total systemic clearance causing an increase in elimination half-life (25-fold, 20 to 492 min). The results demonstrate that the large differences in the total systemic clearance and half-life of these glycopeptide antibiotics are primarily due to dramatic differences in serum protein binding and notto differences in the intrinsic elimination processes (enzymes or transport proteins). It appears that the same physical-chemical properties that govern the protein binding and pharmacokinetics of small organic molecules govern the disposition of these high-molecular weight glycopeptide antibiotics.     

Structure-pharmacokinetic relationships among the N1,N3-alkylxanthines in rats.

The pharmacokinetics of four N3-alkylxanthine and four N1-methyl-N3-alkylxanthine derivatives has been investigated in rats after intravenous administration of the individual alkylxanthines. The concentration of N1,N3-alkylxanthine in plasma and urine was determined by HPLC. A one-compartment model adequately described the plasma concentration time data. The steady-state volume of distribution (Vss) was calculated using model-independent methods. The relation between Vss and unbound drug fraction in plasma (fu) was significantly correlated (Vss = 0.844fu + 0.119; r = 0.999, P less than 0.01), indicating that the differences in fu among these xanthine derivatives is mainly responsible for differences in Vss. The decrease in Vss and increase in plasma protein binding with lipophilicity reflected a relatively constant tissue affinity. The total body clearance increased with lipophilicity with the exception of the first three lower congeners which were almost completely excreted unchanged in urine, mainly via active tubular secretion. Renal elimination was markedly reduced by the presence of a methyl group at the N1-position. Renal clearance decreased with increasing lipophilicity, due to increased tubular reabsorption whereas non-renal (hepatic) clearance increased with increasing lipophilicity.     

Systemic pharmacokinetics of acitretin, etretinate, isotretinoin, and acetylenic retinoids in guinea pigs and obese rats.

Etretinate, a highly lipophilic retinoid, is known to accumulate in the human body with a slow systemic elimination (half-life approximately 100 days) after long-term treatment. Retinoids with high lipophilicity and slow body elimination have the propensity of eliciting teratogenic effects. Therefore, synthetic retinoids with reduced systemic retention are desired. In this study, we evaluated the systemic pharmacokinetics of acitretin, etretinate, isotretinoin, synthetic acetylenic retinoic acids (AGN 190121, AGN 190186, and AGN 190299), and acetylenic retinoates (AGN 190073, AGN 190089, and AGN 190168) in guinea pigs following iv doses. Their pharmacokinetics were also measured in obese rats to probe the effect of body fat on the drug disposition of retinoids. The acetylenic retinoates were hydrolyzed to their corresponding free acids at a much faster rate than etretinate in both animal species. All retinoates showed faster body clearance and larger volume of distribution than their free acids. In the obese rats, longer elimination half-lives and slower body clearance of the retinoids, except isotretinoin, were observed as compared to those in the normal rats. These results suggest that body fat has a significant effect on drug disposition and slows down the systemic clearance of retinoids. Since the synthetic acetylenic retinoates rapidly converted to their less lipophilic free acids after systemic absorption, the potential accumulation of these retinoids, as reported for lipophilic etretinate, were unlikely to occur in humans and animals.     

Comparative pharmacokinetics of coumarin anticoagulants XV: relationship between pharmacokinetics of dicumarol and warfarin in rats.

The distribution, elimination, and anticoagulant effect of dicumarol and warfarin were determined in adult males rats following intravenous injection of single doses of these drugs in crossover experiments. The biological half-life of dicumarol ranged from 5 to 28 hr; that of warfarin ranged from 9 to 30 hr. There was a statistically significant correlation between the following pharmacokinetic characteristics of dicumarol and warfarin in individual animals: biological half-life, apparent volume of distribution, total plasma clearance, and concentration in plasma eliciting one-half the maximum anticoagulant effect (effective concentration). The mean ratio of the respective biological half-lives (warfarin/dicumarol) was 1.42, and that of the apparent volumes of distribution was 1.50. The ratio of the effective plasma concentrations (dicumarol/warfarin) was correlated negatively with the half-life of dicumarol and positively with the ratio of the half-life values (warfarin/dicumarol) in individual animals. Additional studies with serum samples from other rats showed pronounced interindividual differences in the serum protein binding of both dicumarol and warfarin and a strong correlation between the protein binding of these two drugs in serum of individual animals. The results of this study, together with the results of previous studies in this series, indicate that serum protein binding is the major determinant of interindividual differences in the pharmacokinetics of dicumarol and warfarin in rats under these experimental conditions.     

The pharmacokinetics of alfentanil in gynecologic surgical patients

The pharmacokinetics and serum protein binding of alfentanil during continuous intravenous infusion were determined in 11 women who were either healthy (American Society of Anesthesiologists [ASA] physical status 1) or had mild systemic disease (ASA physical status 2). Anesthesia was induced with intravenous thiopental 2 mg/kg and alfentanil 50 micrograms/kg and maintained with constant intravenous alfentanil infusions of 1-3 micrograms/kg/min until approximately ten minutes before the end of surgery. Venous blood samples were obtained after the bolus of alfentanil was administered and at various times during and after the alfentanil infusion. Serum alfentanil concentrations were measured by gas-liquid chromatography. There was considerable interpatient variability in alfentanil pharmacokinetics and serum protein binding. The mean +/- SD alfentanil serum clearance, volume of distribution at steady state (Vss), and elimination half-life were 5.2 +/- 2.0 mL/min/kg, 0.47 +/- 0.1 L/kg, and 97 +/- 52 minutes, respectively. The mean fraction of alfentanil unbound in serum (fu) was 0.18 +/- 0.08. There was a time-dependent decrease in alfentanil serum clearance that correlated with increasing duration of surgery. This decrease in clearance resulted in a prolonged alfentanil half-life. These results indicate there is considerable interpatient variability in the pharmacokinetic parameters and serum protein binding of alfentanil in these patients and suggest that the infusion rate of alfentanil during maintenance anesthesia should be adjusted for individual patient response. Infusion rates may need to be tapered during prolonged operations.     

Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and 14C-disopyramide

The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of 14C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10(-7) M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7 X 10(5) M-1 and 4.4 X 10(5) M-1, respectively (p less than 0.05). The unbound clearance of disopyramide averaged 277 ml/min and 209 ml/min in normal subjects and in patients (p less than 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p less than 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.     

Comparative pharmacokinetics of coumarin anticoagulants. XIV: relationship between protein binding, distribution, and elimination kinetics of warfarin in rats.

The relationships between the protein binding, distribution in the body, and kinetics of elimination of warfarin were studied. Individual rats eliminated warfarin by apparent first-order kinetics, with a biological half-life of 5.9-41 hr and a total plasma clearance of 2.4-22 ml kg(-1) hr(-1). There is a strong positive correlation between the apparent volume of distribution (Vd) and the elimination rate constant (kel). There was no apparent concentration dependance of warfarin binding to serum proteins over a wide concentration range, but there were pronounced intersubject variations in protein binding, with the free fraction of drug (f) in serum ranging from 0.172 x 10(-2) to 1.53 x 10(-2). There are strong positive correlations between f and kel, f and Vd, and f and the kidney-serum concentration ratio of warfarin. Consistent with theory, there is an excellent positive linear correlation between f and total plasma clearance of the drug. The intersubject variation in f is not related to variations in serum albumin or total protein concentration. There is a strong correlation between values of f for serum and liver homogenate in individual animals, consistent with the lack of correlation between f in serum and the liver-serum concentration ratio of warfarin. These results show that the pronounced intersubject variation in the elimination of warfarin observed in this investigation was related to interindividual differences in plasma protein binding of the drug. The differences in protein binding cannot be ascribed to differences in plasma protein concentrations and may reflect configurational differences of proteins or the presence of an endogenous displacing agent at different concentrations.     

Stereoselective aspects in the pharmacokinetics and pharmacodynamics of acenocoumarol and its amino and acetamido derivatives in the rat

The stereoselectivity of the pharmacokinetics and of the pharmacodynamics of the oral anticoagulant acenocoumarol (AC) and of two of its potential metabolites, the amino (AM) and the acetamido (AA) derivatives, were investigated in the rat. The pharmacokinetics and pharmacodynamics were investigated following the acute subcutaneous (1 mg/kg) administration of the pure enantiomers. For AC and AA, the S(-)-enantiomer was preferentially eliminated, whereas for AM the R(+)-enantiomer showed the shortest half-life. The differences in elimination between the AC enantiomers were entirely due to differences in total clearance, 183 +/- 14 and 714 +/- 148 ml X h-1 X kg-1 (+/- SD) for R(+)- and S(-)-AC. Also the differences in elimination between the AM enantiomers were mainly due to differences in body clearance, 50 +/- 13 and 18 +/- 4 ml X h-1 X kg-1 for R(+)- and S(-)-AM. For S(-)-AA the higher total clearance as well as the smaller volume of distribution accounted for its 2-fold higher rate of elimination. Acetylation of AM, i.e. the conversion to AA, which accounted for about 50% of its total clearance was stereoselective for R(+)-AM. The renal clearance of AA which accounted for 50-60% of the AA clearance was not selective for one of the AA enantiomers. Stereoselectivity in plasma protein binding was observed, the differences, however, were small. Thus, stereoselectivity in plasma protein binding did not account for the observed differences in the pharmacokinetics. The differences in anticlotting activity between the enantiomers of AC and AM were determined mainly by their pharmacokinetics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Single- and multiple-dose pharmacokinetics, kidney tolerability and plasma protein binding of tenoxicam in renally impaired patients and healthy volunteers

The 20 mg single-dose and 12 days repeated-dose pharmacokinetics of tenoxicam and the 5-OH-tenoxicam metabolite have been evaluated in healthy volunteers and two groups of patients with different degree of renal impairment, in total 20 persons. Concomitantly, the plasma protein binding of tenoxicam and the effects of treatment on renal function were evaluated. No differences were found between the investigated groups in the pharmacokinetics of total tenoxicam and the 5-OH metabolite did not interfere either with the pharmacokinetics or with the plasma protein binding of tenoxicam. A positive correlation was found between an increase in the free fraction (% F) of tenoxicam in plasma and a decrease in the plasma elimination half-life in the low creatinine clearance group (40-20 ml/min.) both after the single-dose and at steady-state. At steady-state, a non-linear correlation was demonstrated between a decrease in the urinary excretion of the 5-OH metabolite and a decrease in creatinine clearance from 130 to 20 ml/min. An increase in the plasma level of the 5-OH metabolite by three times was found in the low creatinine clearance group as compared to healthy subjects. 14C-Impurities of tenoxicam, as low as 1.2%, were shown to greatly influence the determination of the plasma protein binding (equilibrium dialysis) of the highly protein-bound tenoxicam due to a non-binding ability of the impurities to plasma proteins. No significant changes in renal parameters were found during the study. It can be concluded that the pharmacokinetics and plasma protein binding of tenoxicam and the pharmacokinetics of the 5-OH-tenoxicam metabolite are increasingly changed in subjects with a creatinine clearance below 40 ml/min. A decreased binding of tenoxicam to plasma proteins in low clearance patients is probably the reason for a faster elimination of tenoxicam in this group rather than a higher intrinsic hepatic metabolic activity. This study conducted in a low number of patients did not bring forward any new data indicating any adverse effects of tenoxicam on renal function.     

Lack of influence of cigarette smoking on triazolam pharmacokinetics.

The influence of cigarette smoking on the pharmacokinetics of a single dose of the triazolobenzodiazepine hypnotic triazolam was evaluated in 12 healthy nonsmoking male volunteers and in 12 male subjects, matched for age, height and weight, who smoked an average of 24 cigarettes a day (range: 15-30). Triazolam kinetics were determined from multiple serum concentrations measured during 15 h after a single 0.5 mg dose. There were no significant differences between nonsmoking controls and cigarette smokers in the peak serum triazolam concentration (4.64 vs 4.73 ng ml-1), the time of peak concentration (0.98 vs 1.0 h after dosage), elimination half-life (2.8 vs 2.5 h), or oral clearance of triazolam (506 vs 627 ml min-1). Likewise there were no significant differences between groups in the extent of triazolam binding to serum protein (18.8 vs 18.5% unbound). Altered pharmacodynamics of triazolam in cigarette smokers are not likely to be explained by altered pharmacokinetics.     

Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers

Plasma pharmacokinetics of a single IV dl-propranolol dose (8 mg) were investigated in 12 obese subjects (mean +/- SD: 110.3 +/- 20.4 kg; 198.7 +/- 32.5% of ideal body weight) and compared with those of 12 healthy subjects (66.7 +/- 6.8 kg; 94.5 +/- 7.8% of ideal body weight). In obese subjects plasma alpha-1 glycoprotein acid concentrations and propranolol protein binding capacity did not differ significantly from control subjects. When compared with controls, obese subjects showed a significant increase (P less than .01) in AUC (161.0 +/- 67.0 vs 109.6 +/- 23.1 hr.micrograms/L), and significant decreases (P less than .01) in Vss (208.9 +/- 71.9 vs 318.6 +/- 91.8 L), V beta (234.3 +/- 70.4 vs 340.7 +/- 89.1 L), and total clearance (57.5 +/- 18.3 vs 75.9 +/- 15.4 L/hr). Elimination half-life was similar for the two populations (3.5 +/- 0.9 hr in obese subjects vs 3.1 +/- 0.9 hr in controls). Therefore, neither lipophilicity of propranolol nor drug plasma protein binding can explain these data. Altered hepatic function and tissue blood flow in obese subjects are proposed as an explanation for the decrease in total clearance and volume of distribution.     

Dose-related pharmacokinetics and pharmacodynamics of valproate in the elderly

Valproate exhibits a complex pharmacokinetic profile due to concentration-dependent protein binding and clearance. It has been shown that the protein binding of valproate decreases as the serum concentration increases in a young adult population. Furthermore, the percentage of protein binding is lower in the elderly compared with young adults at comparable low therapeutic serum concentrations. The extent of valproate protein binding at higher concentrations in the elderly has not been described. Studies conducted in the elderly have found unbound valproate clearance to be decreased compared with younger adults, although these changes in clearance have not been evaluated at higher therapeutic serum concentrations. We evaluated the pharmacokinetics of valproate (protein binding and clearance) across a wide dosage range in the elderly and measured the impact of this on drug-related side effects using a single-blind within-subject study design in 6 healthy elderly volunteers (aged 65-76 years). Steady-state total and unbound serum valproate concentrations were assessed at 3 doses: 500, 1000, and 1500 mg/d. As doses and valproate serum concentrations increased, the unbound fraction (10.0%, 13.0%, 17.4%) and total clearance (4.8, 6.0, 6.7 mL/h/kg) increased, respectively. Unbound clearance decreased (49.4, 45.8, 39.4 mL/h/kg) with increasing valproate serum concentrations. Drug-induced CNS effects and nausea severity scores correlated with total and unbound serum valproate concentrations. Significant dose-dependent changes in valproate pharmacokinetics were observed in the elderly.     

Factors involved in the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer: clinical and experimental studies

COL-3 is an oral, lipophilic, tetracycline analog that has been administered to patients with metastatic cancer. Preliminary assessment of COL-3 in 35 patients with refractory metastatic carcinoma demonstrated apparent nonlinear pharmacokinetics with highly variable oral clearance (63.9% coefficient of variance [CV]). To elucidate possible sources of variability of COL-3 pharmacokinetics in vivo, in vitro plasma protein binding and in vitro metabolism were explored along with in vivo pharmacokinetics using compartmental modeling. The variability in the overall clearance and urinary excretion of COL-3 was also assessed. COL-3 had a long terminal half-life (median = 59.8 h), large apparent volume of distribution (median = 50.2 L), and low apparent clearance (median = 9.93 mL/min). Only adjusted ideal body weight decreased the variability in total apparent clearance. There was nonsaturable plasma protein binding of COL-3 (fu = 5.5%), with the majority of binding to albumin. The renal route of elimination is negligible, with 0.06% of unchanged COL-3 and 3.31% COL-3 glucuronide excreted in the first 6 days. COL-3 is not metabolized by phase I metabolism but does undergo glucuronidation in vitro by UGT1A1, UGT1A3, UGT1A9, and UGT2B7 and in vivo, as evidenced by COL-3 glucuronides in the urine (median = 13.6% of the total dose). COL-3 exhibits nonlinear pharmacokinetics, possibly due to dissolution rate-limited absorption.     

Disease-induced changes in the plasma binding of basic drugs

The plasma binding of basic (cationic) drugs differs from that of the more completely studied acidic drugs. Basic drugs associate with a number of plasma constituents. alpha 1-Acid glycoprotein, lipoprotein, and albumin all appear to play an important role in the binding of most of these drugs. Acidic drugs bind largely to albumin. The variation in plasma albumin is relatively narrow and is almost always in the direction of decreased concentrations. alpha 1-Acid glycoprotein and lipoproteins show large fluctuations due both to physiological and pathological conditions. Decreases and increases in concentration have been observed. Associated with these changes in binding proteins, both decreases and increases in plasma binding of basic drugs have been recorded. Increased binding with disease appears to be virtually unique to basic drugs. The implications of these newly described disease-induced increases in plasma binding have yet to be explored. With the limited information in hand the following consequences are predicted. Increased binding will tend to decrease the volume of distribution of total (bound plus free) drug. The clearance will be unchanged or decreased depending upon the initial clearance of the drug and the avidity of the protein binding. As the half-life depends upon both clearance and volume of distribution, changes in it will be variable, depending upon changes in these two parameters. It is predicted that the area under the free drug plasma concentration-time curve will decrease with increasing binding after an intravenous dose while it will be unchanged after an oral dose. The relationship of total drug plasma concentration to free drug concentration will change with changes in binding. Thus plasma concentration monitoring of drug therapy by use of total drug concentrations will be inaccurate in situations in which large variations in binding occur. Misinterpretations of both therapeutic monitoring and pharmacokinetics studies in disease states with altered binding are likely unless these changes are appreciated.     

Disopyramide pharmacokinetics and bioavailability following the simultaneous administration of disopyramide and14C-disopyramide

The pharmacokinetics and bioavailability of total (bound plus unbound) and unbound disopyramide were compared following the simultaneous administration of an oral dose of disopyramide and an intravenous dose of¹⁴C-disopyramide in five normal volunteers and in 11 patients with congestive heart failure. The binding of disopyramide varied between 60 and 92% in patients and between 81 and 88% in normal subjects at postequilibrium drug concentrations of 10^–7M. The binding of disopyramide to serum protein was concentration-dependent in all study subjects at serum concentrations achieved following drug administration. The association constant for the first binding site in serum from normal subjects and patients averaged 8.7X10⁵ M^–1 and 4.4X10 ⁵ M^–1, respectively (p < 0.05). The unbound clearance of disopyramide averaged 277ml/min and 209 ml/min in normal subjects and in patients (p < 0.05). When normalized for body weight, the unbound clearance between patients and normal subjects was not significantly different. The elimination half-life of unbound concentrations in normal subjects and in patients averaged 4.9 and 6.1 h, respectively (p < 0.05). The clearance and elimination half-life of total disopyramide was the same in both groups. Although the bioavailability of disopyramide averaged 0.85 in both groups, it was more variable in patients owing to the variability in the fraction of the dose absorbed. The unbound renal clearance and volume of distribution at steady state of disopyramide was related to cardiac index. The ratio of elimination half-lives of total and unbound disopyramide was related to the extent of serum protein binding.This work was supported by Grant GM-28424 from the National Institute of General Medical Sciences, National Institutes of Health.     

Phenobarbital pharmacokinetics and salivary and serum concentrations in pregnancy

The pharmacokinetics and the ratio between salivary and serum concentrations of phenobarbital (PB) were determined in 10 women undergoing treatment in late pregnancy. An approximately 2.5-fold variation was measured in the apparent relative clearance rates of PB in the women studied. The means of the total clearance rate (0.255 L/h), the relative clearance rate (4.0 ml/h/kg of body weight), the elimination half-life (95 h), the elimination rate constant (0.0071/h), and the apparent volume of distribution (35.49 L) were within the ranges observed in nonpregnant subjects. The PB concentration in saliva was 34% of that in serum. Salivary and serum levels of PB correlated closely with each other. Serum gamma-glutamyl transpeptidase activity increased, and total bilirubin concentrations decreased during PB treatment, both of which can be linked to the PB-caused hepatic microsomal enzyme induction phenomenon. The variation in clearance rate emphasizes the importance of close monitoring of PB treatment of pregnant women. The results suggest that salivary PB measurements can be used with sufficient accuracy to predict PB concentrations in the serum and to optimize PB treatment during pregnancy.     

Oxaliplatin: pharmacokinetics and chronopharmacological aspects

Oxaliplatin is the first clinically available diaminocyclohexane platinum coordination complex. The drug is non-cross-resistant with cisplatin or carboplatin and is one of the few active drugs against human colorectal cancer. Its cytotoxicity is synergistic with fluorouracil and folinic acid (leucovorin), the reference treatment for this disease. The main cumulative dose-limiting toxicity of oxaliplatin is peripheral sensory neuropathy. The drug can also produce diarrhoea, vomiting and haematological suppression. Unlike cisplatin, no renal failure or peripheral motor neuropathy have been reported and the sensory neuropathy is partly reversible. Unlike carboplatin, oxaliplatin produces only mild to moderate haematological toxicity. Oxaliplatin undergoes biotransformation into aquated forms in the blood, where 3 species can be found: total platinum, ultrafilterable or 'free' platinum and erythrocyte platinum. Flameless atomic absorption (FAAS) is used for assaying platinum concentration in various tissues. Inductively-coupled plasma mass spectrometry (ICP-MS), with a >10-fold lower sensitivity threshold than FAAS, was also used for the determination of oxaliplatin pharmacokinetics. The pharmacokinetics of oxaliplatin are described by a 3-compartment model. The drug rapidly crosses the cellular membrane as a result of its lipophilicity. Hence, at the end of a 2-hour infusion, approximately 40% of the blood platinum is found in erythrocytes. The distribution half-life of ultrafiltrated plasma platinum ranges from 10 to 25 minutes and its terminal elimination half-life is 26 hours (determined with FAAS) or 270 hours (ICP-MS). The elimination half-life of erythrocytic platinum is 12 to 50 days, close to that of erythrocytes. 30 to 50% of the platinum is recovered in the urine within 2 to 5 days, with renal clearance accounting for half of the total clearance of ultrafiltrated platinum. The total clearance of this species is correlated with the glomerular filtration rate. No pharmacokinetic-pharmacodynamic relationship has been established for oxaliplatin. Pharmacokinetic alterations produced by fluorouracil + folinic acid or irinotecan were minimal if any. The prolonged stability of oxaliplatin makes it suitable for continuous infusions over 4 to 5 days, with a delivery rate which can be either constant or chronomodulated (peak rate at 1600h), using programmable ambulatory pumps. Chronomodulation significantly reduces toxicity and improves antitumour activity as compared with constant rate infusion. These differences in pharmacodynamic properties were paralleled by differences in plasma concentration time courses. The different drug concentration profiles achieved with different infusional modalities may be useful tools for understanding the relationship between the pharmacokinetics and pharmacodynamics of oxaliplatin and may lead to further optimisation of its administration schedule and its combination with other drugs.     

Pharmacokinetics of lithium carbonate in children

The pharmacokinetics in both serum and saliva of a single oral dose of lithium carbonate 300 mg was investigated in nine children aged 9 to 12 years. The serum and saliva concentration-time curves were parallel and biexponential, with a fast distribution phase after the peak at the second hour and a slow elimination phase starting from the 12th hour. The fast phase half-life was 6.0 +/- 1.8 hour in the serum, and 5.8 +/- 1.9 hour in the saliva. The slow phase half-life was 17.9 +/- 7.4 hour in the serum and 15.6 +/- 8.2 hour in the saliva. Lithium was 2.84 +/- 0.86 times higher in the saliva than in the serum, with a saliva/serum r coefficient of correlation of 0.93. A relatively large error was found in predicting serum levels from saliva. There were significant intersubject differences in the saliva/serum ratio, which point to the need for individual ratios in clinical use. On the whole, the pharmacokinetics of lithium in children had the same features as in adults, with a trend toward a shorter elimination half-life and higher total clearance.     

Dose-dependent stereopharmacokinetics of 5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sulfonamide-7,7 -dioxide , a potent carbonic anhydrase inhibitor, in rats.

[5,6-dihydro-4H-4(isobutylamino)thieno(2,3-B)thiopyran-2-sul fonamide-7,7- dioxide] (MK-927), a potent carbonic anhydrase inhibitor capable of reducing intraocular pressure after topical application, is currently under investigation for the treatment of glaucoma. The purpose of this study was to characterize the pharmacokinetics of the enantiomers of MK-927 with particular emphasis on the effect of dose on the elimination kinetics. Because the drug resided primarily in erythrocytes, the kinetic analysis was generally performed based on the drug concentration of whole blood. Following iv administration, the rat cleared the (R)(-)-enantiomer more rapidly than the (S)(+)-isomer. The stereoselective difference in elimination kinetics was dose-dependent; total blood clearance of the (R)(-)-enantiomer was approximately 40 times that of the (S)(+)-isomer at 0.05 mg/kg, and about 7-fold at 5 mg/kg. For both enantiomers, the pharmacokinetic parameters remained unchanged when the dose increased from 0.05 to 0.2 mg/kg, while the total blood clearance and apparent volume of distribution increased substantially as the dose exceeded 2 mg/kg. Nevertheless, the terminal half-life for each enantiomer appeared to be dose-independent. The enantiomers were extensively bound to erythrocytes in a stereoselective manner; at low concentrations, the (S)(+)enantiomer was bound 3-fold more strongly than the (R)(-)-enantiomer in vitro and 6-fold in vivo. Clearly, the magnitude of stereoselectivity in the elimination kinetics of MK-927 enantiomers (40-fold) cannot be explained solely by stereoselective binding. Thus, other factors may also contribute to the overall stereoselectivity in the elimination kinetics of MK-927. The dose-dependent kinetics of the enantiomers was probably due to the saturable binding to carbonic anhydrase.     

Quinolone pharmacokinetics

Fluoroquinolones have broad antibacterial spectra and are active against most Gram-negative and many Gram-positive species. They exhibit excellent oral bioavailability, extensive tissue penetration, low protein binding, and a long elimination half-life. This review compares and contrasts the pharmakonetics of some quinolone antibiotics - especially pefloxacin, ciprofloxacin, enoxacin, norfloxacin, ofloxacin, fleroxacin and lomefloxacin - in terms of their adsorption, distribution, metabolism, elimination, and interactions with other drugs and with food. In addition, the pharmacokinetics of these agents in the elderly and in patients with renal or hepatic impairment is discussed. The fluoroquinolones are established as a major class of antibiotics in the treatment of infections but pharmacokinetics factors should be considered when deciding on the most appropriate of these agents to use in individual patients.