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M G Wientjes

Publications and source records attributed to M G Wientjes.

At least 55 records · Page 3Linked to original sources
PubMed1995

Design and analysis of in vitro antitumor pharmacodynamic studies.

The relationship between drug concentration (C), exposure time (t), and the resulting effect (h) for a chemotherapeutic agent is expressed as Cn x t = h. The value of n, derived from curve fitting of the C versus t plot, indicates the relative importance of concentration and exposure time. The selection of concentrations and exposure times in a pharmacodynamic experiment may affect the precision and accuracy of parameter estimation. The use of optimal designs is even more critical when the numbers of experimental conditions are limited by tumor availability (e.g., small size of surgical specimens from patients). The present study used computer-simulated data to define the most efficient in vitro pharmacodynamic experimental designs and the optimal method of pharmacodynamic data analysis. All studies used Monte Carlo simulations to compare designs with varying numbers of drug concentrations, exposure times, and replications. For each selected design, 50-100 error-containing data sets were created by addition of experience-based random errors to expected concentration-response profiles. To compare methods of data analysis, the same 1250 simulated data sets were analyzed by two methods (i.e., surface response method and traditional method). The results showed that simultaneous fitting of drug effect at all concentrations and all exposure times by the surface response method yielded n estimates that had greater precision and accuracy than a traditional method that required sequential determination of the effective inhibitory concentration (e.g., IC50) and then the n value using the IC50 at different exposure times. Subsequent studies were analyzed using the surface response method. To evaluate the effect of selection of concentrations and exposure times on the precision of n estimation, between 1100 and 2200 simulated data sets, with 400 observations per data set, were generated using different exposure times and drug concentrations. Because the number of observations was limited to 400, the number of replications at each condition varied depending on the total number of selected conditions.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Agents↗
PubMed1995

Use of drug kinetics in dermis to predict in vivo blood concentration after topical application.

PURPOSE: To use the drug kinetics in dermis to predict the in vivo blood concentration after topical administration. METHODS: A two-step pharmacokinetic model was established. The first step was to calculate the drug input rate or flux from the skin to the systemic circulation using the drug kinetic parameters in dermis. These parameters include (a) distance over which the drug concentration declines by 50%, (b) drug concentration at the epidermal-dermal junction, and (c) minimal plateauing drug concentration in the muscle layer. These parameters were experimentally determined from the drug concentration-tissue depth profiles in the dermis, after the application of a topical dose of ddI (200 mg/kg) to rats. The second step was to use the drug input rate together with the systemic disposition pharmacokinetics of ddI in rats to predict the plasma concentration-time profiles. The model-predicted plasma concentration-time profiles were compared with the observed profiles, to determine the validity of the proposed pharmacokinetic model. RESULTS: The observed steady state concentration (CSS) in individual animals (n = 6) deviated from the predicted values by 3 to 55% with 3 of 6 rats showing a < 15% deviation. The mean observed CSS of all animals deviated from the mean predicted values by less than 15%. CONCLUSIONS: The close agreement between the observed and the model-predicted drug concentrations indicates that the systemic drug input can be calculated from the drug kinetics in the dermis.

Administration, Topical↗
PubMed1995

Extensive absorption of 2',3'-dideoxyinosine by intratracheal administration in rats.

PURPOSE: To evaluate the intratracheal route of administration as an alternative to oral administration for 2',3'-dideoxyinosine (ddI). METHODS: A ddI dose (40 mg/kg/300 microliters or 6.5 mg/kg/50 microliters) was instilled into the trachea in female Fisher rats and an intravenous tracer dose (9 micrograms/kg) of 3H-ddI was administered concomitantly to determine the drug clearance. Plasma concentrations were analyzed for the rate and extent of absorption. RESULTS: ddI was rapidly absorbed from the lungs, with a bioavailability of 63% at 40 mg/kg and 101% at 6.5 mg/kg. By comparison, our previous data showed an oral bioavailability of about 15% (Pharm Res., 9:822, 1992). The distribution of a dye solution instilled intratracheally showed that a fraction of the 300 microliters dose spilled over to the gastrointestinal tract, where the entire 50 microliters dose was retained in the lungs. The different distribution of the two doses volumes likely contributed to the different bioavailability, with a fraction of the higher dose/volume degraded in the gastrointestinal tract after the spillover. Absorption of ddI from the airspace of the lung was biexponential, suggesting two absorption processes. CONCLUSIONS: These data indicate significantly higher and less variable bioavailability of ddI by the intratracheal route of delivery compared to the oral route. Furthermore, the complete bioavailability at the lower dose/volume indicates no significant pulmonary first pass elimination for ddI.

Absorption↗
PubMed1995

Penetration kinetics of 2',3'-dideoxyinosine in dermis is described by the distributed model.

The present study evaluated the kinetics of drug penetration in the dermis. A rat was given a dermal dose of 2',3'-dideoxyinosine (ddI). At 6 hr, the skin tissue was excised, immediately frozen and sectioned, and the decline of drug concentration as a function of tissue depth was determined. The tissue concentration-depth profile showed a semilogarithmic decline, as would be expected in a distributed tissue kinetic model which incorporates diffusion and capillary membrane transport. The goodness of fit of the profiles by the simple diffusion and the distributed models were compared using four statistical criteria, i.e., coefficient of determination. Akaike Information criterion, Schwartz criterion and Imbimbo criterion. These analyses showed that the decline of tissue concentration versus tissue depth in the dermis was better described by the distributed model than by the diffusion model in all 7 animals. To examine the effect of blood perfusion on the tissue concentration-depth profiles, some of the tissues were frozen after 1 and 2 hr storage at room temperature. In contrast to the adjacent tissues frozen immediately, the concentration-depth profiles in tissues frozen after a 1-2 hr delay were described equally well by distributed and diffusion models. A comparison of the concentration-depth profiles in the tissues processed immediately or after a delay showed a 7 fold more shallow slope and a 60% lower concentration at the epidermis-dermis interface after storage. However, storage did not alter the total amount of drug in the entire dermis. Drug degradation during storage was further ruled out by the insignificant ddI degradation in 10% skin homogenate (a half-life of approximately 70 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Histocultures of human prostate tissues for pharmacologic evaluation.

This study evaluated the growth of human prostate tumors in histoculture, an in vitro culture technique that maintains three-dimensional tissue structure and organization. Eighty-six percent of 50 tumor specimens from 50 patients were successfully cultured. The histocultures showed proliferation of epithelial tumor cells and stromal cells. Prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) were detectable by immunohistochemistry for at least 8 weeks. Synthesis of PSA was further confirmed by its presence in medium. The mean thymidine labeling index (LI) of the neoplastic cells was 62%. There was no correlation between thymidine LI and tumor grade. The explants maintained their characteristics for at least 8 weeks as indicated by unchanged thymidine LI, PSA and PAP immunohistochemistry after 2 and 8 weeks in culture. A 24 to 48 hour delay in processing the tissues for culture did not reduce the thymidine LI. The thymidine LI and PSA and PAP staining in tumors cultured in a Minimal Essential Medium (MEM)-based or a PFMR-4-based culture medium were similar, suggesting an insignificant effect of the medium on cell proliferation. Migration of neoplastic cells from the tissue fragments into the collagen gel matrix was noted in 1 of 10 samples cultured in MEM-based medium versus 8 of 10 samples cultured in PFMR-4 medium (p < 0.01). Exposure of 13 patient tumors to suramin, doxorubicin and 5-fluorouracil at clinically relevant concentrations and duration showed tumor sensitivity in 23%, 31% and 15% of the specimens. These values approximate the historical clinical response rates. These data suggest that the histoculture system holds promise for short-term culture of human patient prostate tumor specimens for biologic and pharmacologic studies.

Acid Phosphatase↗
PubMed1994

Tissue pharmacokinetics of 2',3'-dideoxyinosine in rats.

The present study examined in rats the concentration-time profiles of 2',3'-dideoxyinosine (ddI) in pharmacologically relevant tissues, including organs where drug effects are desired (brain, lymph nodes, spleen), organs with known drug toxicity (pancreas), and major eliminating organs (liver, kidney). ddI was analyzed by high performance liquid chromatography and radioimmunoassay. In the liver, pancreas, spleen, brain and lymph nodes, the highest concentrations were reached between 4 and 7 min after drug administration. The concentrations subsequently declined in parallel with those in plasma, indicating that plasma and these tissues were in rapid equilibrium. The concentrations in these tissues were less or equal to that of plasma. In the kidney, the maximal concentration occurred at a later time of 14 min, after which concentrations also declined in parallel to those in plasma. The kidney concentrations were about 10-fold greater than plasma concentrations. The ratios of tissue-to-plasma concentrations and of areas under the tissue and plasma concentration-time profiles showed a 230- to 300-fold range with the rank order of kidney >> liver approximately pancreas > lymph nodes > spleen >> brain, with respective values of 10.4, 1.09, 0.90, 0.75, 0.42, and 0.04. These data indicate no accumulation of ddI in brain, lymph nodes, spleen, pancreas and liver, and a significant accumulation in the kidney. The low tissue-to-plasma ratios in brain and spleen and a moderate ratio in lymph nodes indicate that further enhancement of the therapeutic effect of ddI requires improved drug delivery and entrapment in these tissues.

Animals↗
PubMed1994

Correlation of human bladder tumor histoculture proliferation and sensitivity to mitomycin C with tumor pathobiology.

This study examined the in vitro proliferation and mitomycin C (MMC) sensitivity of patient bladder tumors as a function of the tumor pathobiology. Surgical specimens of transitional cell carcinoma of the bladder were maintained as histocultures on collagen gels. The thymidine labeling index (LI) was determined by autoradiography and the labeling for proliferating cell nuclear antigen (PCNA) by immunohistochemistry. There was a linear correlation between the thymidine LI and the PCNA LI, but the PCNA LI were quantitatively lower than the thymidine LI. The mean thymidine LI were 30.9, 32.4 and 51.5% for the grade I, II and III tumors, 33.6 and 56.3% for the superficial (Tis, Ta and T1) and invasive (T2-T4) tumors, and 28.9 and 50.9% for the diploid and aneuploid tumors. Analysis of variance indicates that these differences were statistically significant. These data indicate that the proliferation of tumor histocultures paralleled the tumor aggressiveness in vivo. The tumor sensitivity to MMC, measured by the inhibition of the thymidine LI of tumor cells, was studied in 31 tumors. At a 2 hour exposure, as is currently used in intravesical therapy, the MMC concentrations required for 50% inhibition of thymidine LI (IC50) showed a 120-fold intertumor variation (0.102 to 12.4 micrograms./ml.). The sensitivity to MMC inversely correlated with tumor aggressiveness. The IC50 increased with tumor LI (p < 0.05). The mean IC50 were 2.61 and 5.79 micrograms./ml. for superficial and invasive tumors (p < 0.05), 1.06, 3.05 and 4.49 micrograms./ml. for grade I, II and III tumors (p < 0.05), and 2.53 and 4.31 micrograms./ml. for diploid and aneuploid tumors (p = 0.14). These data indicate a large difference in sensitivity of human bladder tumors to MMC, with greater sensitivity for well-differentiated superficial tumors and lesser sensitivity for undifferentiated, invasive tumors.

Autoradiography↗
PubMed1994

Pharmacokinetics of intravesical doxorubicin in superficial bladder cancer patients.

The urine and plasma pharmacokinetics of intravesical doxorubicin were studied in 8 patients with a history of superficial bladder cancer. Patients received 6 weekly treatments of 40 mg. doxorubicin in 20 ml. physiological saline. Doxorubicin was detectable (0.2 ng./ml. or more) in plasma from 6 of 8 patients during the initial treatment. The maximal concentrations ranged from 0.5 to 4.5 ng./ml. (mean 1.4). Doxorubicin was not detected in plasma from 7 of 8 patients during treatment 2 and not detected in any patient during treatment 4. The doxorubicin concentrations in urine decreased to approximately 50% at 5 minutes after dosing due to dilution by post-catheterization residual urine, and decreased by a further 6-fold by the end of the 2-hour treatment due to urine production. The recovery of doxorubicin at the end of treatment averaged 88.3%, with an additional recovery of 3.7% during the subsequent 4 hours. Urinary pH (range 5.5 to 8.5) did not affect the stability nor the systemic absorption of doxorubicin. In conclusion, we found that for intravesical doxorubicin therapy there was insignificant systemic exposure to doxorubicin, the highest systemic absorption from the bladder occurred shortly after surgery, there was high target site (bladder tissue) specificity, insignificant metabolism and/or degradation of doxorubicin, and dilution of urinary doxorubicin concentrations and, therefore, decreased tumor exposure to the drug due to residual urine and urine production.

Administration, Intravesical↗
PubMed1993

Penetration of mitomycin C in human bladder.

The penetration of mitomycin C (MMC) in bladder tissue was studied in patients who received intravesical chemotherapy at the time of radical cystectomy. An intravesical dose of MMC (20 mg/40 ml) was instilled and maintained in the bladder for 60 to 120 min at which time the solution was drained. Within 10 to 60 min after draining the drug solution, the bladder vasculature was ligated, and the bladder was removed. Tissues were sectioned serially in layers parallel to the urothelium and analyzed for MMC concentration. Of the 24 patients evaluated, 17 patients had a low final MMC concentration in urine (< 66 micrograms/ml) or had the MMC solution drained more than 30 min before ligation of the blood vessels. Among these 17 patients, the concentration in the urothelium was measurable in only 4 patients, while the concentrations in deeper tissues were not measurable. In the remaining 7 patients where the urine concentration was > 120 micrograms/ml and where the vasculature was ligated within 30 min after the MMC solution was drained, the bladder wall contained significant MMC concentrations. The drug penetration was studied in the latter 7 patients, using sections of bladder wall that were grossly normal and non-tumor bearing. Concentrations in the bladder wall declined semilogarithmically with tissue depth from the urothelium to the deep muscle and reached a plateau at about 2000 microns depth. The median MMC concentrations were 5.6 micrograms/g in the urothelium and lamina propria interface, 2.7 micrograms/g in the lamina propria, and 0.9 microgram/g in the muscularis. The distance over which the MMC concentration decreased by one-half was about 500 microns. The concentration ratio between the urine and urothelium/lamina propria interface was about 35-fold. The mean plasma concentrations were 0.003, 0.1, and 0.4% of the mean concentration in urine, urothelium, and the averaged bladder tissue concentrations, respectively. Paired superficial tumor and normal tissues were obtained from 5 bladders. In 4 of 5 cases, the concentration in tumors was higher than in normal tissues, while the reverse was seen in the remaining tumor. In one sessile bladder tumor a complete concentration-depth profile could be obtained. While the concentrations in the tumor tissue were 2-3-fold higher than that in the adjacent normal tissue, the rate of concentration declined with respect to tissue depth and hence the distance over which the MMC concentration decreased by one-half was similar in both tumors.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Intravesical↗
PubMed1993

Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer.

Treatment of superficial bladder cancers by intravesical mitomycin C (MMC) chemotherapy gives a varying and incomplete response. Our recent pharmacokinetics and pharmacodynamics studies have shown that treatment effectiveness is limited by drug degradation in acidic urine and by drug dilution due to residual urine volume and urine production. A model was developed to predict drug exposure in tumors in the bladder wall and to correlate drug exposure with antitumor effect. The model is based on the known pharmacokinetic data in patients treated with intravesical chemotherapy, drug-penetration data in the bladder wall of patients undergoing radical cystectomy, and pharmacodynamic data on patients' bladder-tumor chemosensitivity. Computer simulations based on the model were generated. The simulations predicted that changes in treatment parameters would affect the therapeutic outcome in the following rank order: dose > residual volume > urine production > dosing volume > urine pH > dwell time. Tissue exposure could be enhanced by increased dose, complete bladder emptying, reduced fluid intake, use of the minimal dosing volume, and alkalinization of the urine to a neutral pH. Increasing the dwell time from 2 to 4 h gave an insignificant improvement and posed a compliance problem. The selected optimized regimen of a 40-mg dose, no residual volume, 0.62-ml/min urine production, a 20-ml dosing volume, and alkaline urine pH yielded a calculated 8.5-fold increase in tissue exposure over that achieved by the standard regimen, which consisted of a 20-mg dose, 32-ml residual volume, 1.5-ml/min urine production, a 20-ml dosing volume, and acidic urine pH. On the basis of previously established pharmacodynamic data, we hypothesize that the increase in tissue exposure in the optimized treatment would result in a 20% improvement over the standard therapy along with an increase in the recurrence-free rate from 56% to 76% of patients. A phase III efficacy trial comparing the optimized and standard regimens is proposed.

Administration, Intravesical↗
PubMed1993

Absorption of 2',3'-dideoxyinosine from lower gastrointestinal tract in rats and kinetic evidence of different absorption rates in colon and rectum.

This study explored the rectal route of administration for 2',3'-dideoxyinosine (ddI). Rats were given a rectal infusion of nonradiolabeled ddI (200 mg/kg in 0.7 mL saline) over 35 min along with an intravenous (iv) bolus injection of [8-(3)H]ddI (20 microCi, equivalent to 2.1 micrograms), which was used to calculate the absolute rectal bioavailability of ddI. Maximal plasma concentrations of rectally administered unlabeled ddI were 5.4 +/- 2.2 micrograms/mL and were reached at the end of the infusion. The rectal bioavailability averaged 15.6 +/- 4.4% (n = 9). The second aim of this study was to examine the kinetics of ddI absorption from the colorectal region. Analyses of the absorption rate-time profiles by the Loo-Riegelman and deconvolution methods showed biphasic absorption: a rapid phase during infusion and a slow phase postinfusion. These profiles were inconsistent with a mammillary model with absorption from a single site with one apparent rate constant. The model which gave the best fit for infusion and postinfusion data consisted of two different sites (colon and rectum) with different apparent absorption rate constants. The two sites were connected by a first-order transfer of drug solution from rectum to colon. The apparent absorption rate constant in the rectum was 39-fold higher than that in the colon. In conclusion, these results show absorption of ddI from the colorectal region and suggest the rectal route as an alternative to the oral route. The data further suggest different absorption sites in the colorectal region, with a more rapid absorption in the rectum than in the colon.

Administration, Rectal↗
PubMed1993

Histocultures of patient head and neck tumors for pharmacodynamics studies.

This investigation was to establish a clinically relevant experimental model to evaluate the pharmacodynamics of drugs used for head and neck cancers. A total of 83 surgical samples of primary and lymph nodal metastatic tumors was obtained from 66 patients. Fragments of these tumors were cultured on a collagen gel matrix. The tumor cell labeling index (LI) was determined by [3H]thymidine incorporation and autoradiography. Seventeen tumors (20%) were contaminated. About 80% of the remaining 65 tumors were successfully cultured for at least 2 weeks. The cultured tumor fragments retained the morphology and architecture of the freshly removed specimens; both tumor and stromal cells were present. The tumor cell LI after 2-3 weeks in culture, determined from the most proliferative area of the tissue, averaged 77 +/- 12% for primary tumors and 78 +/- 12% for nodal metastases. The activity of three clinically active agents, 5-fluorouracil (FU), cisplatin (DDP), and mitomycin C (MMC), was evaluated in 47 tumors. All three drugs inhibited the tumor LI. The concentrations needed to produce a 50% inhibition of the tumor LI (IC50) were within the clinically achievable concentration range. The intertumor variation in the IC50 for FU (60-fold) was considerably greater than that for DDP and MMC (7- to 8-fold). The nodal metastatic tumors appeared to be less sensitive to FU than the primary tumors, while there were no apparent differences for DDP or MMC.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Gastrointestinal and hepatic first-pass elimination of 2',3'-dideoxyinosine in rats.

We previously reported a > 80% presystemic loss of 2',3'-dideoxyinosine (ddl) in rats after an oral dose. The present study investigated the extent of drug loss due to incomplete absorption and presystemic elimination by intestinal wall, liver and intestinal microflora. In vitro metabolism by tissue homogenates showed that the extraction by liver, duodenum, jejunum and ileum was 19.0, 0.5, 1.8 and 1.4%, respectively. Hence, metabolism by the intestinal wall contributed less to the first-pass metabolism than the liver. The in vivo first-pass elimination was determined by infusing ddl into the liver and different parts of the intestinal tract. The in vivo extractions of 12 and 200 mg kg-1 of ddl doses by the liver were 23 and 5%, indicating a concentration-dependent liver metabolism. The in vivo liver extraction at the low dose was similar to the in vitro extraction. The in vivo extraction was 10% in the duodenum and 73% in the ileum. The significantly higher in vivo intestinal extractions compared to the in vitro extractions indicate a loss due to factors in addition to intestinal wall enzyme metabolism. Incomplete absorption was ruled out, based on the undetectable excretion of ddl in feces after duodenal or ileal infusion. A 14% w/v solution of intestinal contents degraded ddl by 18 and 38% over 2 and 24 hr, respectively, at 37 degrees C. By linear extrapolation, a 100% w/v enzyme solution would degrade the entire dose within 1.5 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Enhancement of bacillus Calmette-Guerin attachment to the urothelium by removal of the rabbit bladder mucin layer.

It has been established that the urothelial mucin layer functions as a bacterial anti-adherence factor. Intravesical Bacillus Calmette-Guerin is used to treat patients with superficial bladder cancer. The proposed mechanism of action of Bacillus Calmette-Guerin is adherence to the urothelium with induction of an immunologic and/or inflammatory response. The current study was designed to determine if rabbit bladder mucin removal results in increased Bacillus Calmette-Guerin urothelial adherence. PAS and colloidal iron stains were used to demonstrate that intravesical instillation of 50% acetone renders rabbit bladder urothelium mucin deficient. The urothelium remains mucin deficient at two hours, but by 24 hours the mucin layer has been regenerated. Two hours following intravesical 3H-labeled Escherichia coli administration, bacterial adherence was 29-fold greater in mucin deficient than mucin intact rabbits (p = 0.05). By 12 hours, the difference in adherence was not significant. Two hours following intravesical administration of 3H-labeled Bacillus Calmette Guerin, mucosal adherence was 21-fold greater in mucin deficient compared to mucin intact rabbits (p = 0.002). After mucin removal, Bacillus Calmette Guerin urothelial adherence was significantly increased. The significant increase in Bacillus Calmette Guerin adherence after mucin removal may be clinically exploitable.

Animals↗
PubMed1992

Nonlinear disposition of intravenous 2',3'-dideoxyinosine in rats.

The pharmacokinetics of 2',3'-dideoxyinosine (ddI) were examined in rats given intravenous doses of 8, 40, or 200 mg/kg. The concentrations of ddI in whole blood and plasma were identical. The concentration decline was multiexponential, with mean half-lives of 2 and 20 min for the first and second phases, respectively. At the highest dose, a slower third phase with a half-life of 56 min was observed. The total-body clearances were 99, 77, and 37 ml/min-kg for the 8, 40, and 200 mg/kg doses. The steady-state volume of distribution showed a trend for a decrease with increasing doses, but the difference was not statistically significant. Twenty-four-hour urinary recovery of unchanged drug for the three doses was similar at about 20%, suggesting that a major fraction of the dose was metabolized. Urinary excretion of ddI metabolite, hypoxanthine, accounted for less than 5% of the dose. Renal and metabolic clearances decreased with increased doses. ddI was metabolized in blood; the addition of inorganic phosphate, a cosubstrate in phosphorylase-mediated nucleoside catabolism, enhanced the degradation by about fourfold. In summary, these data indicate equal distribution of ddI in the extracellular and intracellular spaces in blood, its enzymatic degradation in blood, and nonlinear elimination kinetics.

Animals↗
PubMed1992

Lack of pharmacokinetic interaction between intravenous 2',3'-dideoxyinosine and 3'-azido-3'-deoxythymidine in rats.

We investigated the pharmacokinetic interaction between 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (ddI), given to rats by intravenous injection. For both compounds, the clearances, terminal half-lives, and fractions of the dose excreted unchanged in urine were not altered by the other drug (P greater than 0.05), indicating no pharmacokinetic interaction between the two drugs.

Animals↗
PubMed1991

Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients.

Intravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer. This study was to establish the intra- and intersubject variabilities in the systemic (plasma) and target site (bladder) exposure to the drug and to identify the factors which contribute to these variabilities. The pharmacokinetics of MMC were studied in 10 patients. Treatment consisted of transurethral tumor resection followed by six weekly intravesical treatments with MMC (20 mg in 40 ml of water). The dosing solution was maintained in the bladder for 2 h. Pharmacokinetic studies were performed at the time of the first, fourth, and sixth or first, second, and fourth treatments with MMC for a total of 28 treatments. Concentration-time profiles of the plasma and bladder contents (i.e., urine), urine volumes, and urine pH were determined during and for up to 4 h after intravesical administration. Maximal plasma MMC concentrations averaged 43 ng/ml (range, 2.1-180.5 ng/ml) in treatment 1. In comparison, the MMC plasma concentration for myelosuppression reported in the literature is 400 ng/ml. Maximal plasma concentrations in treatments 2, 4, and 6 were at least 4-fold lower than those in treatment 1 and in most cases were below the detection limit of 0.5 ng/ml. This indicates that the absorption of MMC during the later treatments was less than in the first treatment given shortly after surgery. Urinary MMC concentrations during instillation declined from 519.4 +/- 34.8 micrograms/ml (mean +/- SD) in the dosing solution to 64.6 +/- 39.4 micrograms/ml 2 h after instillation. Thus, the superficial bladder tissue was exposed to drug concentrations 300- to greater than 34,000-fold higher than the plasma-perfused systemic tissues. Intravesical exposure to MMC, as determined by the area under the urine concentration-time curve, showed large intra- and intersubject variabilities (range, 2,185-40,411 micrograms-min/ml). Pharmacokinetic analysis showed that the bladder exposure to MMC inversely correlated with the residual urine volume at the time of drug administration (P less than 0.001), the urine production rate (P = 0.05), and the rate of drug removal by degradation and absorption during therapy (P less than 0.01). At the end of the 2-h treatment, recovery of MMC from the bladder instillate ranged from 1 to 100% and correlated with the urine pH at the time of removal (P less than 0.001). At pH between 5 and 5.5, less than 30% of the dose was recovered.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Intravesical↗