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Dive into the research topics where Thomas M. Ludden is active.

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Featured researches published by Thomas M. Ludden.


Clinical Pharmacokinectics | 1991

Nonlinear pharmacokinetics : clinical implications

Thomas M. Ludden

SummaryNonlinear pharmacokinetics (in other words, time or dose dependences in pharmacokinetic parameters) can arise from factors associated with absorption, first-pass metabolism, binding, excretion and biotransformation. Nonlinearities in absorption and bioavailability can cause increases in drug concentrations that are disproportionately high or low relative to the change in dose. One of the more important sources of nonlinearity is the partial saturation of presystemic metabolism exhibited by such drugs as verapamil, propranolol and hydralazine. In such cases, circulating drug concentrations are sensitive not only to dose size but also to rate of absorption: slower absorption may decrease the overall systemic availability.The binding of drugs to plasma constituents, blood cells and extravascular tissue may exhibit concentration dependence. This can cause pharmacokinetic parameters based on total blood or serum drug concentrations to be concentration-dependent. Often, in these cases, parameters based on free drug concentration appear linear. An important consideration in regard to concentration-dependent serum binding is the difficulty in relating total concentration to a usual therapeutic range if free concentration is a better indicator of drug effect. Measurement of free concentration is needed in these cases, particularly if the intersubject variability in binding is high. An example of this behaviour is valproic acid.Partial saturation of elimination pathways can result in the well known behaviour typical of Michaelis-Menten pharmacokinetics. Small changes in dosing rate can make much larger differences in steady-state concentration. The time to achieve a given fraction of steady-state becomes longer as the dosing rate approaches the maximum elimination rate. Alcohol and phenytoin are examples of drugs that exhibit such behaviour. The sensitivity of steady-state concentration and cumulation rate to changes in dosing rate are both influenced by the magnitude of parallel firstorder elimination pathways: even a first-order pathway that is only 1 to 2% of maximum clearance (which occurs at very low concentration) can be an important determinant of steady-state concentration and cumulation rate when concentrations are high. Theophylline and salicylate have significant parallel first-order elimination pathways as well as saturable pathways.Autoinduction causes an increase in clearance with long term administration. In some cases, dosage adjustment must be made to compensate for the increase, and the possibility that the degree of induction may be dose- or concentration-dependent must be kept in mind. Carbamazepine is a major example of autoinduction.It is fortunate that only a few of the many hundreds of drugs in use exhibit nonlinear behaviour that leads to clinical implications. An understanding of the causes of nonlinearity and the influence of such behaviour on concentration-time profiles is required if such drugs are to be used safely and efficaciously.


Clinical Pharmacology & Therapeutics | 1977

Individualization of phenytoin dosage regimens

Thomas M. Ludden; John P. Allen; William A. Valutsky; Ana V. Vicuna; Jean M. Nappi; Stephen F. Hoffman; Jack E. Wallace; David Lalka; J. L. McNay

Two methods for arriving at optimum, individual phenytoin dosage regimens have been evaluated in 12 patients. (1) Individual Michaelis‐Menten pharmacokinetic parameters for phenytoin were estimated from two reliable steady‐state phenytoin serum concentrations resulting from different daily doses: The observed steady‐state phenytoin serum levels obtained after 3 to 8 wk of compliance with dosage regimens calculated from the individual pharmacokinetic parameters agreed well with predicted levels (r = 0.824, p < 0.02). The average deviation between observed and predicted levels was 0.04 µg/ml (range, ±3.2 µg/ml). (2) A previously published nomogram for making adjustments in phenytoin dosage regimens: The serum phenytoin concentration actually expected from the dose indicated by the nomogram was calculated using individual pharmacokinetic parameters. The daily dose for one patient would have exceeded his estimated maximal rate of metabolism. The correlation between calculated and predicted phenytoin serum levels in the other 11 patients was weak but significant (r = 0.360, p < 0.05). The average deviation was −3 µg/ml (range, 3.9 to −11.3 µg/ml). It was concluded that the use of individual pharmacokinetic parameters is practical and is also superior to the nomogram.


Journal of Pharmacokinetics and Biopharmaceutics | 1985

Population pharmacokinetics of racemic warfarin in adult patients

Dennis Mungall; Thomas M. Ludden; James Marshall; David W. Hawkins; Robert L. Talbert; Michael H. Crawford

The population pharmacokinetics of racemic warfarin was evaluated using 613 measured warfarin plasma concentrations from 32 adult hospitalized patients and 131 adult outpatients. Warfarin concentrations were measured in duplicate using a high-performance liquid chromatographic procedure. The pharmacokinetic model used was a one-compartment open model with first-order absorption (absorption rate constant set equal to 47 day−1) and first-order elimination. The extent of availability was assumed to be one. A linear regression model was used to evaluate the influence of various demographic factors on warfarin oral clearance. Age appeared to be an important determinant of warfarin clearance in this adult population. There was about a 1%/year decrease in oral clearance over the age range of 20–70 years. Smoking appeared to result in a 10% increase in warfarin clearance, while coadministration of the inducers phenytoin or phenobarbital yielded about a 30% increase in clearance. This study has yielded a predictive model that, when combined with appropriate pharmacological response data, may be useful in the design and adjustment of warfarin regimens.


Clinical Pharmacology & Therapeutics | 1983

Effect of erythromycin on carbamazepine kinetics

Yan Yan Wong; Thomas M. Ludden; Rodney D. Bell

Two recent reports of carbamazepine‐induced intoxication during concurrent therapy with macrolide antibiotics prompted us to perform a carefully controlled two‐way cross‐over study in eight healthy male nonsmokers. Treatment A was 250 mg erythromycin every 6 hr for 5 days before and 3 days after 400 mg carbamazepine. Treatment B was 400 mg of carbamazepine alone. One half of the subjects received treatment A, then B, while the other half received treatment B, then A. There was a 4‐wk washout period between treatments. Plasma samples obtained at various times up to 72 hr after the carbamazepine dose were assayed in duplicate by HPLC. The data were fit to a one‐compartment open model with first‐order absorption and elimination. Clearance of oral carbamazepine was lower in the presence of erythromycin (mean ± SD, 0.290 ± 0.074 and 0.360 ± 0.072 l · kg−1 · day−1). There were no differences in apparent volume of distribution (1.01 ± 0.20 and 1.04 ± 0.12 l · kg−1), elimination rate constant (0.302 ± 0.113 and 0.348 ± 0.079 day−1), or absorption rate constant (14.5 ± 8.7 and 15.5 ± 16.6 day−1) between the two treatment groups. The decrease in clearance of oral carbamazepine secondary to erythromycin indicates that further clinical studies are warranted.


Clinical Pharmacology & Therapeutics | 1980

Hydralazine kinetics after single and repeated oral doses

Alexander M. M. Shepherd; Thomas M. Ludden; J. L. McNay; Min Shung Lin

In reports on hydralazine kinetics plasma hydralazine levels have been measured with nonspecific assay techniques. The techniques used also include acid‐labile hydralazine metabolites and therefore markedly overestimate hydralazine levels. We have developed specific, sensitive assay methods for the measurement of hydralazine and its major plasma metabolite, hydralazine pyruvic acid hydrazone (HPH). By these methods, we determined hydralazine and HPH kinetics after single and repeated oral doses of hydralazine in eight hypertensive patients. Hydralazine bioavailability in the fast acetylator group (9.5% single dose, 6.6% repeated doses) and in the slow acetylator group (31.3% single dose, 39.3% repeated doses) was phenotype dependent. Peak plasma levels were lower than those reported with nonspecific assays: 0.32 μM for the single dose and 0.14 μM for repeated doses in the fast acetylator group and 1.03 μM for the single dose and 0.96 μM repeated doses in the slow acetylator group. There was no alteration in kinetics and no cumulation in plasma on repeated administration. HPH plasma levels were proportional to those of hydralazine in both acetylator groups and were 2.5 to 4 times as high as those of hydralazine. Elimination half‐lifes were phenotype independent, ranging from 4 to 6 hr. HPH cumulated in the rapid but not in the slow acetylator group after repeated doses of hydralazine.


Clinical Pharmacology & Therapeutics | 1980

Displacement of phenytoin from plasma binding sites by salicylate

D G Fraser; Thomas M. Ludden; Ronald P. Evens; Earl W Sutherland

Six healthy male subjects received phenytoin sodium as 9 100‐mg capsules alone or with aspirin in a randomized, crossover fashion. Aspirin, 975 mg every 6 hr, was started 22 hr before a phenytoin dose and continued for an additional 48 hr during blood sampling. Mean 4‐hr plasma salicylate levels ranged from 104 to 157 μg/ml during the sampling period. Individual mean values for the free fraction of salicylate varied from 0.107 to 0.167. The fraction of free phenytoin in plasma rose from 0.128 ± 0.004 to 0.163 ±0.009 when aspirin was given (p < 0.001). Subjects had lower total phenytoin 48‐hr area under the curve (AUC) values when on aspirin (323 ± 36 without and 261 ± 49 μg · hr · ml−1 with aspirin; p < 0.001) but free phenytoin AUC values were unchanged (41.4 ± 4.5 and 42.4 ±9.0 μg · hr · ml−1; p > 0.5). Thus, more rapid clearance of total phenytoin probably compensated for salicylate displacement of phenytoin from plasma protein binding sites. Total phenytoin levels for therapeutic monitoring must be interpreted cautiously when patients also receive salicylate.


Cancer Chemotherapy and Pharmacology | 1986

Pharmacokinetic study of fludarabine phosphate (NSC 312887)

Marla R. Hersh; John G. Kuhn; Jerry L. Phillips; Gary M. Clark; Thomas M. Ludden; Daniel D. Von Hoff

SummaryCharacterization of the pharmacokinetics of 2-FLAA has been completed in seven patients receiving 18 or 25 mg/m2 daily x5 of 2-FLAMP over 30 min. Assuming 2-FLAMP was instantaneously converted to 2-FLAA, the plasma levels of 2-FLAA declined in a biexponential fashion. Computer fitting of the plasma concentrationtime curves yielded an average distribution half-life (t1/2α) of 0.60 h and a terminal half-life (t1/2β) of 9.3 h. The estimated plasma clearance was 9.07±3.77 l/h per m2 and the steady state volume of distribution, 96.2±26.0 l/m2. There was a significant inverse correlation between the area under the curve (AUC) and absolute granulocyte count (r=-0.94, P<0.02). A relationship between creatinine clearance and total body clearance was noted, but was not statistically significant (r=0.828; P<0.1). Aproximately 24%±3% of 2-FLAA was excreted renally over the 5-day course of drug administration.


Clinical Pharmacology & Therapeutics | 1980

Hydralazine kinetics in hypertensive patients after intravenous administration

Thomas M. Ludden; A. M M Shepherd; J. L. McNay; M. S. Lin

Previous studies on intravenous hydralazine kinetics have been performed using nonselective analytical techniques that measure not only hydralazine but also certain hydralazine metabolites such as hydralazine pyruvic acid hydrazone (HPH). We studied the time course of hydralazine and HPH in eight hypertensive patients after 0.3 mg/kg intravenously with selective high‐pressure liquid chromatographic assays. “Apparent” hydralazine concentrations were also determined using a nonselective gas‐liquid chromatographic procedure. Total plasma clearance, CLT[72.9 ±4.9 (SEM) ml · min−1 · kg−1], apparent volume of distribution, Vdarea (5.83 ± 0.30 l · kg−1), steady‐state volume of distribution, Vdss(1.83 ± 0.17 · kg−1), and terminal half‐life, t½ (53.7 min, harmonic mean) were independent of acetylator phenotype. The high CLT is compatible with rapid intravascular conversion of hydralazine to HPH and a high hepatic extraction ratio. Peak HPH concentrations occurred 10 to 60 min after dose; mean HPH t½ was 239 min. “Apparent” hydralazine concentrations were usually highest in the 2‐min plasma sample and declined with a mean t½ of 296 min. Reports based on nonselective assay methods have underestimated CLT, Vdss, and Vdarea and have overestimated the t½ of hydralazine.


Cornea | 1997

Ocular penetration and pharmacokinetics of topical fluconazole.

Richard W. Yee; Christine J. Cheng; Swaminathan Meenakshi; Thomas M. Ludden; Jack E. Wallace; M G Rinaldi

The high bioavailability and low toxicity of fluconazole, a stable, water-soluble, low-molecular-weight bis-triazole antifungal, makes it a good candidate for consideration as a topical ocular agent. The penetration of fluconazole (0.2%) into the corneas and aqueous humors of New Zealand white rabbits was assayed by gas liquid chromatography (GLC). Peak corneal levels occurred essentially immediately at 5 min in the corneas [debrided, 8.2 +/- 1.2 micrograms/g; nondebrided, 1.6 +/- 0.6 microgram/g; (mean +/- SEM)] and at 15 min after application in the aqueous [debrided, 9.4 +/- 2.3 micrograms/ml; nondebrided, 1.6 +/- 0.6 microgram/ml; (mean +/- SEM)]. Estimating from semilogarithmic plots of the data, the halflife (t1/2) in the debrided eyes was 15 min; in the nondebrided eyes, t1/2 was 30 min. A loading dose of a 20-microliter drop per min for 5 min yielded levels of 59.9 +/- 11.3 micrograms/g (mean +/- SEM) in the debrided corneas and 32.4 +/- 1.9 micrograms/ ml (mean +/- SEM) in the corresponding aqueous humor. A regimen consisting of this loading dose followed by one 20 microliters drop/h for 6 h showed 45.9 +/- 3.5 micrograms/g (mean +/- SEM) in the debrided corneas and 8.8 +/- 1.7 micrograms/ml (mean +/- SEM) in the corresponding aqueous. The same regimen yielded values of 3.1 +/- 0.2 micrograms/g in the nondebrided corneas and 1.3 +/- 0.2 micrograms/ml (mean +/- SEM) in the aqueous. Minimal inhibitory concentrations (MIC) at 24 h for yeasts ranged from < 1.25 to 20 micrograms/ml, for hyaline molds from 2.5 to > 20 micrograms/ml, and dematiaceous molds from < 1.25 to > 20 micrograms/ml. Topical fluconazole exhibits pharmacokinetics and selective MICs that merit further evaluation for its ophthalmic use as a topical antifungal agent.


Hypertension | 1981

Plasma concentration and acetylator phenotype determine response to oral hydralazine.

Alexander M. M. Shepherd; J. L. McNay; Thomas M. Ludden; M. S. Lin; G. E. Musgrave

SUMMARY The vasodepressor response to single and multiple oral doses of hydralazine, 1 mg/kg, was studied in hypertensive patients. The concentration of bydralazbe in plasma was measured both by a newly developed specific and a nonspecific assay similar to those used in previous studies. Acetylator phenotype was determined following oral sulfamethazine. Plasma hydralazine concentration peaked at 1 hour after administration and was undetectable 2 hours later. Apparent hydralazine was present in plasma in higher concentration and for a longer duration than hydralazine. The peak decreases in blood pressure (BP) were proportional to plasma hydralazine concentration following administration of both single and multiple doses and were substantially maintained for 8 hours. In contrast there was no significant correlation between decreases in BP and apparent hydralazine concentrations. The plasma concentration of hydralazine after a standard oral dose varied by as much as 15-fold among individuals and was lower in rapid than slow acetylator phenotype patients. The BP responses were positively correlated with plasma hydralazine concentrations and inversely correlated with acetylator indices. Low plasma concentrations may account for poor responses of some patients to conventional oral doses of hydralazine. The applicability of acetylator pbenotyping for individualization of hydralazine dosage regimens merits further evaluation.

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Alexander M. M. Shepherd

University of Texas Health Science Center at San Antonio

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J. L. McNay

University of Texas at Austin

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M. S. Lin

University of Texas at Austin

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Michael H. Crawford

Royal Prince Alfred Hospital

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Dennis Mungall

University of Texas Health Science Center at San Antonio

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John P. Allen

University of Texas Health Science Center at San Antonio

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Robert L. Talbert

University of Texas at Austin

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David W. Hawkins

University of Texas Health Science Center at San Antonio

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John G. Kuhn

University of Texas Health Science Center at San Antonio

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L.K. Ludden

University of Texas Health Science Center at San Antonio

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