Peak Drug Levels Research Articles

Ciprofloxacin penetration into extravascular spaces in a rabbit model.

Ciprofloxacin penetration into extravascular spaces was studied in a rabbit Visking chamber model. The drug was administered (7 mg/kg) intramuscularly every 4 h for eight doses. Peak and trough drug levels by dose 8 were 1.3 and 0.35 micrograms/ml in serum and 0.61 and 0.50 micrograms/ml in extravascular sites. The ratio of extravascular site to serum free drug area under the drug curve by dose 8 was 91.1%. This potent, new antimicrobial agent appears to distribute freely to extravascular spaces in this animal model.

Clinical pharmacokinetics of high-dose mitomycin C.

The pharmacokinetic profile of high-dose mitomycin C was determined in blood plasma and urine of twelve patients with advanced malignancies in a program including autologous bone marrow transplantation. A total dose of 60 mg/m2 was given, either as a single 60-min infusion or divided into infusions of 30 mg/m2 on each of 2 days or 15 mg/m2 on each of 4 days. One group was given 15-min infusions. Samples of blood plasma and urine were analyzed by high-performance liquid chromatography. Drug concentrations in plasma followed a biphasic pattern, with a terminal elimination half-life of 45 min. This half-life value and other parameters were unaffected by dose level, infusion time, and repeated doses. The lower peak plasma concentrations following 30 mg/m2 given as 60-min infusions compared to the same dose given over 15 min may have accounted for a dramatic drop in the incidence of a severe hemorrhagic colitis. Mitomycin C was excreted in urine at about the same rate as it was eliminated from plasma, but a larger percentage of the dose appeared in urine after 15-min infusions than after 60-min infusions. The pharmacokinetic profile, together with clinical observations, suggests that the dose-limiting toxicity of mitomycin C may be related to peak drug levels, and that both these levels and the toxicity are lessened as the infusion time is increased.

Clinical experience with rate-controlled delivery of antihypertensive therapy by a transdermal system

The efficacy of transdermal clonidine, alone and in combination with diuretics, has been demonstrated in several studies involving patients with mild to moderate essential hypertension. In one 3-month open study, 64% of patients (wearing one to three 3.5 cm 2 transdermal patches) achieved sustained blood pressure reductions throughout the treatment period. In this large study, side effects requiring discontinuation of drug were not observed. Transdermal clonidine reduced plasma renin activity and urinary aldosterone excretion to the same extent as that reported for oral clonidine. Renal function or serum electrolytes were not affected during therapy with transdermal clonidine. Another study showed that patients receiving oral clonidine and hydrochlorothiazide experienced comparable blood pressure reductions when switched to transdermal patches. Plasma drug concentrations measured during treatment with the transdermal patches were similar to the trough levels observed during treatment with oral clonidine. The equipotency of oral and transdermal therapy in combination with hydrochlorothiazide was also demonstrated in two remaining studies. In one of these studies it was suggested that daily variations in blood pressure induced by the peak and trough drug levels of the oral form were minimized by the stable drug levels characteristics of the transdermal device.

Neurochemical effects of minaprine, a novel psychotropic drug, on the central cholinergic system of the rat.

Minaprine, a novel psychotropic drug with antidepressant, anticataleptic and antiaggressive properties, produced an increase in rat brain regional acetylcholine content at a subconvulsant dose of 30 mg/kg IP. The greatest increase (60%) was produced in the striatum, whereas an increase of about 35% was obtained in the hippocampus and the rest of the cortex. A small but significant increase of 14% was also found in the midbrain-hindbrain region. Minaprine decreased choline content only in the striatum. No tolerance to acute challenge was observed after 10-day chronic treatment. In vitro, the drug had no effect on striatal choline acetyltransferase activity up to a concentration of 160 microM and only weakly displaced (3H) dexetimide from its specific muscarinic receptor binding sites in striatum (IC50, 2 X 10(-4) M). After in vivo administration the drug did not affect sodium-dependent high affinity choline uptake by a hippocampal homogenate. On the other hand, the drug inhibited both striatal and hippocampal acetylcholinesterase activity at high (40-160 microM) concentrations in vitro. In vivo the drug produced a brief (5 min), small (18%) decrease in the enzymic activity which corresponded in time to the peak drug level attained in the brain, but was not concomitant with a change in striatal acetylcholine content. By contrast, the increase in striatal acetylcholine appeared after 30 min when there was no longer inhibition of acetylcholinesterase activity and when the level of minaprine in brain was reduced by 78%. Blockade of dopamine receptors by pimozide pretreatment partially prevented the increase in striatal acetylcholine produced by minaprine, whereas interference with cholinergic or serontonergic neurotransmission was without effect.(ABSTRACT TRUNCATED AT 250 WORDS)

The Aminoglycoside Panel

The aminoglycoside antibiotics gentamicin and tobramycin have been monitored traditionally by measuring peak and trough drug levels in serum. We found interpretation of these data to be hazardous, due to variations in the drug administration-specimen collection process and routine medical events and practices. We describe an aminoglycoside panel consisting of three serum levels drawn across one dosage interval. Gentamicin and tobramycin were measured by an enzyme immunoassay. 430 panels (1,290 samples) were evaluated by determining each panel's conformity to a classical monoexponential decay curve. Panels were then categorized by pattern of fit to this model. Sixty-two percent of the panels fell within acceptable limits of the model, while 13% displayed obvious errors. The percentage of acceptable panels on nursing units given an intensive educational program on the proper protocol for drug administration-specimen collection procedures was increased compared with the rest of the hospital. We propose the adoption of the aminoglycoside panel for the routine monitoring of these antibiotics as a means of gauging specimen and data quality.

Clinical pharmacology of tiamulin in ruminants.

Median values for the minimum inhibitory concentrations (MIC) of tiamulin for Mycoplasma and Acholeplasma isolated from ruminants were 0.05 micrograms/ml and 0.025 micrograms/ml, respectively. These values were close to the MIC values of tylosin and considerably lower than the respective values for spectinomycin, Spiramycin and oxytetracycline. The serum concentration--time profile of tiamulin after intramuscular (i.m.) injection to goats, ewes, cows and calves, and after oral administration to preruminant calves was characterized by a rapid absorption phase (absorption t1/2 of less than 30 min.), a short plateau phase, an elimination t1/2 ranging between 3 and 6 h, and low peak serum drug levels. The serum elimination t1/2 of the drug after intravenous (i.v.) injection was 25 min. It appears that tiamulin is extensively metabolized in ruminants and is well distributed throughout the body. Drug concentrations in the lungs, liver, and the kidneys 1 h after i.v. injection were four to seven times higher than in blood. The drug penetrated very rapidly into the milk after i.m. administration; mean peak drug concentrations in normal milk and in milk secreted from inflamed glands of cows were 7.5 times and 1.2 times higher respectively, than the mean peak serum drug concentrations. Concentrations of tiamulin of potential therapeutic value in the treatment of mycoplasmal infections can be maintained in the lungs for at least 12 h after i.m. injection at 10 mg/kg, and in preruminant calves after an oral dose of 20 mg/kg. However, tiamulin possesses several very serious side-effects and the i.v. route of administration is definitely contraindicated.

Pirmenol kinetics and effective oral dose.

The oral form of pirmenol has not been administered to man. Pirmenol was given by mouth to eight patients with chronic, stable premature ventricular beats (PVBs) to determine effective dose and kinetics. The patients were evaluated with a dose-ranging protocol following by a double-blind, crossover, placebo-controlled study of doses that were effective during dose ranging. Oral doses of 150 to 250 mg induced at least 90% suppression of PVBs 18 of the 19 times they were administered during both protocols. During the double blind experiment, a single oral dose of pirmenol suppressed 95 +/- 8% PVBs/hr (mean +/- SD) for 3 consecutive hr, while placebo suppressed 4 +/- 42% PVBs/hr (P less than 0.01). a 90% or greater reduction in PVBs persisted for a median of 6 hr (range 1 to 8 hr). The range of plasma pirmenol concentrations associated with an at last 90% reduction in PVBs was 0.7 to 2.0 micrograms/ml. Median half-life (t1/2) was 9.3 hr (range 6.0 to 12.4) with 86.6 +/- 2.4% protein binding and 82.6 +/- 23.6% bioavailability. At peak drug level there was lengthening of the QTc interval (0.036 sec, P less than 0.05), but no change in heart rate, blood pressure, PR interval or QRS duration, or symptoms. In this single-dose study, pirmenol effectively reduced PVBs, has a relatively long t1/2, and was minimally toxic.

Peak drug levels in linear pharmacokinetic systems--III. Multimodal impulse responses in multicompartment systems.

This paper deals with the unimodality of the ‘impulse response’ in compartmental systems, where the ‘impulse response’ in any given compartment is the time course of the amount of diffusing substance in that compartment after an initial instantaneous injection of the substance into that or some other compartment. It is shown that in certain compartmental structures, with injection in certain compartments, the impulse response is always unimodal or monotonic in all compartments, regardless of the numerical values of the various transfer rate coefficients. Structures with this property are here named ‘UM structures’, and they include the familiar mammillary and catenary structures. In this paper, the set of all UM structures is described. Structures which are not UM (NUM structures) are identified by showing that, by removal of certain connections and compartments according to certain rules, they can be reduced to small structures which can be shown to be NUM by numerical computation. Computations on two systems with bimodal impulse responses show that with constant infusions of a fixed amount of substance the peak level may increase paradoxically with decrease in the infusion rate over a certain range. This effect is extremely small, however.

Bioavailability of Regular and Controlled-Release Chlorpheniramine Products

The bioavailability of chlorpheniramine regular-release versus controlled-release products was compared using 15 human subjects. The dosage forms evaluated were an 8-mg barrier coated-bead capsule, an 8-mg repeat action tablet, two 4-mg tablets, and 4- and 8-mg syrups. Single doses of each product were administered orally in a 5-way crossover study, plasma samples were collected at specific time intervals, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The average plasma elimination half-life of chlorpheniramine was calculated to be ~18.3 hr. The controlled-release products gave a higher Cmax than the 4-mg syrup, but <two 4-mg tablets. The controlled-release products also extended the time necessary to attain peak drug levels compared to the 4- and 8-mg syrups. The area under the curve (AUC) data for the controlled-release products was not equivalent to equal amounts of the regular-release products. The study indicated that while the controlled-release chlorpheniramine products were successful in prolonging the time course of absorption, this was at the expense of incomplete bioavailability of the drug.

Peak drug levels in linear pharmacokinetic systems—III. Multimodal impulse responses in multicompartment systems

Peak drug levels in linear pharmacokinetic systems—III. Multimodal impulse responses in multicompartment systems

Peak drug levels in linear pharmacokinetic systems--I. Effect of rate of injection.

This paper presents three theorems on the peak drug levels that result from injection into a linear pharmacokinetic system. As a preliminary, the “rate of injection” is defined in terms of time expansion or time contraction of the injection function (input). The first theorem then states that the peak drug level will not be greater when the rate of injection is slow than when it is fast, if the impulse response is unimodal. The second theorem sets limits for the time of the maximum drug level, in relation to the time of the maximum of the (unimodal) impulse response and the duration of the input. The third theorem defines conditions which assure a definitely lower peak drug level if the rate of injection is slower. A graphical method is suggested for determining the times and magnitudes of the peak drug levels that result from constant infusions of a fixed dose at different rates. An example is provided to show that if the impulse response is multimodal then the peak drug level may sometimes increase with a decrease in the injection rate.

Peak drug levels in linear pharmacokinetic systems--II. Conditions for a paradoxical injection rate effect with rectangular input.

The preceding paper (Thorn, 1981) has shown that in a linear pharmacokinetic system with a multimodal impulse response the peak drug level may sometimes be smaller with slower rates of injection. This paper presents two theorems on this paradoxical injection rate effect where the injection is a constant infusion of finite duration. The first theorem establishes a graphical method for determining whether a given impulse response will give a paradoxical injection rate effect; and the second establishes that the maximum paradoxical increase in peak drug level is by a factor of two. It is further shown that in order to approach this maximum paradoxical increase the impulse response must contain two isolated, sharp, narrow pulses of approximately equal area. Some examples of bimodal arterial dye-dilution curves from the literature are discussed as impulse responses; and there is also a discussion of the behavior of drug level maxima and minima at different injection rates.

Peak drug levels in linear pharmacokinetic systems—I. Effect of rate of injection

Peak drug levels in linear pharmacokinetic systems—I. Effect of rate of injection

Peak drug levels in linear pharmacokinetic systems—II. Conditions for a paradoxical injection rate effect with rectangular input

Peak drug levels in linear pharmacokinetic systems—II. Conditions for a paradoxical injection rate effect with rectangular input

The pharmacokinetics of trichlormethiazide in hypertensive patients with normal and compromised renal function.

The pharmacokinetics of trichlormethiazide (TCZ) was studied in twelve patients after a single 4 mg dose. Seven patients had normal renal function with creatinine clearance greater than 90 ml/min. Five patients had compromised renal function with creatinine clearances averaging 48 +/- 29 ml/min. The TCZ plasma half life and area under the plasma concentration-time curve (AUC) were significantly greater in patients with impaired function, compared to patients with normal renal function. There were no significant differences between the two patient groups in terms of either rate of drug absorption or total urinary recovery of unchanged drug. Furthermore, there was no correlation between peak drug levels or AUC and renal excretion of water or electrolytes.

The metabolic disposition of etodolac in rats, dogs, and man.

The metabolic disposition of etodolac (etodolic acid) was studied after oral and intravenous administration of the 14C-labeled or unlabeled drug to rats and dogs, and after oral administration of the drug to man. In all species, peak serum drug levels were attained within 2 hr after dosing. In rats and dogs, virtually all of the oral dose was absorbed; etodolac represented 95% of the serum radioactivity in rats and 75% in dogs. Serum levels in all species were generally dose-related. The elimination portion of the serum drug concentration/time curves was characterized by several peaks, which in rats were shown to be due to enterohepatic circulation. Tissue distribution studies in rats showed that radioactivity localized primarily in blood vessels, connective tissue, and highly vascularized organs (liver, heart, lung, and kidney) and that the rate of elimination of radioactivity from tissues was similar to that found in the serum. The apparent elimination half-life of etodolac averaged 17 hr in rats, 10 hr in dogs, and 7 hr in man. Etodolac was extensively bound to serum proteins. Liver microsomal cytochrome P-450 levels were unaltered in rats given etodolac daily for 1 week. The primary route of excretion in rats and dogs was via the bile into the feces. Preliminary biotransformation studies in dogs showed the presence of the glucuronide conjugate of etodolac in bile, but not in the urine. Glucuronide conjugates were not seen in the rat. Four hydroxylated metabolites in rat bile were tentatively identified. It was concluded that, in rats and dogs, etodolac is well absorbed, is subject to extensive enterohepatic circulation, undergoes partial biotransformation, and is excreted primarily into the feces.U

Age-related differences in response to ethanol in the rat

Female rats, aged 2–3, 11–12, and 18–20 months were tested for cin old rats, but blood alcohol levels at time of awakening were lowest in older, compared with younger animals, suggesting a greater responsiveness of brain tissues to the hypnotic effects of ethanol in older rats or, alternatively, a more rapid development of central acute tolerance in younger subjects. Lower doses of ethanol (.75–1.5 g/kg) were observed to produce greater hypothermia and impairment of motor performance in older animals. Although blood alcohol levels were higher in older animals following the injection (1 g/kg, IP) of ethanol, there was no age-related effect on rate of ethanol disappearance. Doses of ethanol that produced comparable blood levels in old (1.0 g/kg) and young (1.5 g/kg) animals also produced a similar degree of motor impairment. Thus, the greater effects produced by moderate doses of ethanol (around 1.0 g/kg) in older rats can be attributed to the higher peak drug levels achieved in those animals. Differential responses to hypnotic doses of ethanol may involve, additionally, a greater responsiveness of brain tissue to that drug in older animals.

Serum phenobarbital and barbital concentrations in rats on a limited food regimen

Serum barbiturate levels were tracked for several hours in food deprived rats given 40, 60 or 80 mg/kg (SC) of either phenobarbital or barbital. All 3 phenobarbital doses produced peak serum drug levels at 1.5 hr postinjection. Serum barbital concentrations peaked 3 hr after both 60 and 80 mg/kg barbital doses while the 40 mg/kg dose produced a stable low drug level throughout the 4 postinjection hours. For both barbiturates administered, 40 mg/kg doses produced lower serum drug levels than either 60 or 80 mg/kg. The differences in serum drug concentrations between the latter two dose levels were inconsistent over time.

Pindolol pharmacokinetics in relation to time course of inhibition of exercise tachycardia.

1 Pharmacokinetics of pindolol were studied in normal subjects given 5, 10 and 20 mg orally and 3 mg i.v. Plasma half time was 2.9 +/- 0.3 (s.e. mean) h for both routes; peak drug levels occurred 1--2 h after ingestion and bioavailability was 53%. Plasma protein binding was 38% and was independent of plasma concentration; the drug was not concentrated in the red cell. 2 Work-heart rate regression lines were calculated from resting heart rate and three grades of 'steady-state' exercise standardized for the maximum work capacity (Wmax) of each subject. The equation was characterized by slope and HR50 (calculated heart rate at 0.5 Wmax). 3 After giving 5 mg i.v. pindolol to produce maximum cardiac beta-adrenoceptor blockade there were differences in inhibition of resting heart rate, slope, HR50 and maximum heart rate suggesting differences in sympathetic components. However, estimates of the degree of inhibition were closely similar for each variable when determined before and after atropinization indicating that the accuracy of estimation was independent of the level of vagal activity. 4 After oral pindolol peak inhibition of resting heart rate, slope and HR50 coincided with peak plasma concentration. Peak reduction of resting heart rate was greatest at the lowest dose, but inhibition of slope and HR50 were similar at all doses. 5 The different heart rate parameters recovered at different rates. After 24 h slope had returned to control, and the residual inhibition of HR50 reflected residual beta-adrenoceptor blockade of resting heart rate, as demonstrated by a shift in isoprenaline-heart rate relationship. 6 Inhibition of HR50 and other exercise parameters were 20% less in the concentration range 5--20 ng/ml than peak inhibition obtained in the range 21--160 ng/ml. The higher potency of pindolol compared with propranolol can be accounted for by the difference in protein binding.

Serum chloramphenicol levels and the intramuscular bioavailability of several parenteral formulations of chloramphenicol in ruminants

Summary Serum chloramphenicol concentrations were determined by microbiological and chemical assay methods in cows, ewes, and goats treated parenterally with seven different veterinary parenteral chloramphenicol products, including the water soluble sodium succinate ester of chloramphenicol and solutions of 20%, 25% and 50% of chloramphenicol base in various organic solvents. Serum drug concentrations were analyzed for the effect of product formulation differences, dosage, whether the drug was administered i.m. at a single body site or to two sites, and the method of assay, on the absorption from the injection site, peak drug levels, and the persistence in serum of effective concentrations of the drug i.e. 5 to 10 ug / ml. Although differences were observed among the 6 products containing chloramphenicol base in respect to absorption rate and peak serum drug levels, and although these differences significantly influenced the persistence of microbiologically-active serum drug concentrations at the level of ≥ 10 μg / ml, they did not at the level of ≥ 5 μg / ml. In the animal species examined, injections given at 2 sites appeared to influence the duration of predetermined serum drug levels more than the differences among the products in respect of the absorption and elimination rates from serum, the peak serum concentrations, and the dose. The shapes of the concentration-to-time curves in cows and ewes injected with the same dose of a given product were essentially the same, but they were different in goats. Serum chloramphenicol concentrations measured chemically after treatment with chloramphenicol base were 20% to 46% higher than those measured microbiologically. For 60 minutes after the sodium succinate ester had been administered i.v. and i.m. to ewes, the chemically determined chloramphenicol levels were more than twice as high as the respective concentrations determined by microbiological assay, but thereafter, the magnitude of those differences was not greater than observed after treatment with chloramphenicol base. Intramuscular bioavailability of the products containing chloramphenicol base injected at 2 sites was rather poor (51% to 80.5%ofthe dose) and even lower values were calculated after injection at a single site. Results are briefly discussed of the effect of dosage form on the persistence of microbiologically effective serum drug levels. A dose of at least 50 mg / kg to be administered i.m. at two sites are essential prerequisits for chloramphenicol therapy in ruminants.