Palliative care provision at a tertiary cancer center during a global pandemic.

COVID-19 was first reported in Wuhan, China, in December 2019; it rapidly spread around the world and was declared a global pandemic by the World Health Organization in March 2020. The palliative care program at the Princess Margaret Cancer Centre, Toronto, Canada, provides comprehensive care to patients with advanced cancer and their families, through services including an acute palliative care unit, an inpatient consultation service, and an ambulatory palliative care clinic. In the face of a global pandemic, palliative care teams are uniquely placed to support patients with cancer who also have COVID-19. This may include managing severe symptoms such as dyspnea and agitation, as well as guiding advance care planning and goals of care conversations. In tandem, there is a need for palliative care teams to continue to provide care to patients with advanced cancer who are COVID-negative but who are at higher risk of infection and adverse outcomes related to COVID-19. This paper highlights the unique challenges faced by a palliative care team in terms of scaling up services in response to a global pandemic while simultaneously providing ongoing support to their patients with advanced cancer at a tertiary cancer center.

The oncology palliative care clinic at the Princess Margaret Cancer Centre: an early intervention model for patients with advanced cancer.

Several recently published randomized controlled trials have demonstrated the benefits of early palliative care involvement for patients with advanced cancer. In the oncology outpatient setting, palliative care clinics are an ideal site for the provision of early, collaborative support, which can be maintained throughout the cancer trajectory. Despite this, access to ambulatory palliative care clinics is limited, even at tertiary cancer centres. Existing programs for outpatient palliative care are variable in scope and are not well described in the literature. We describe the development and expansion of an outpatient palliative care clinic at the Princess Margaret Cancer Centre, Toronto, Canada, demonstrating how the clinic functions at a local and regional level. This clinic served as the intervention for a recent large cluster-randomized trial of early palliative care. The model for this service can be adapted by other palliative care programs that aim to provide early, integrated oncology care.

Physician and Artificial Intelligence Chatbot Responses to Cancer Questions From Social Media.

Importance: Artificial intelligence (AI) chatbots pose the opportunity to draft template responses to patient questions. However, the ability of chatbots to generate responses based on domain-specific knowledge of cancer remains to be tested. Objective: To evaluate the competency of AI chatbots (GPT-3.5 [chatbot 1], GPT-4 [chatbot 2], and Claude AI [chatbot 3]) to generate high-quality, empathetic, and readable responses to patient questions about cancer. Design, Setting, and Participants: This equivalence study compared the AI chatbot responses and responses by 6 verified oncologists to 200 patient questions about cancer from a public online forum. Data were collected on May 31, 2023. Exposures: Random sample of 200 patient questions related to cancer from a public online forum (Reddit r/AskDocs) spanning from January 1, 2018, to May 31, 2023, was posed to 3 AI chatbots. Main Outcomes and Measures: The primary outcomes were pilot ratings of the quality, empathy, and readability on a Likert scale from 1 (very poor) to 5 (very good). Two teams of attending oncology specialists evaluated each response based on pilot measures of quality, empathy, and readability in triplicate. The secondary outcome was readability assessed using Flesch-Kincaid Grade Level. Results: Responses to 200 questions generated by chatbot 3, the best-performing AI chatbot, were rated consistently higher in overall measures of quality (mean, 3.56 [95% CI, 3.48-3.63] vs 3.00 [95% CI, 2.91-3.09]; P < .001), empathy (mean, 3.62 [95% CI, 3.53-3.70] vs 2.43 [95% CI, 2.32-2.53]; P < .001), and readability (mean, 3.79 [95% CI, 3.72-3.87] vs 3.07 [95% CI, 3.00-3.15]; P < .001) compared with physician responses. The mean Flesch-Kincaid Grade Level of physician responses (mean, 10.11 [95% CI, 9.21-11.03]) was not significantly different from chatbot 3 responses (mean, 10.31 [95% CI, 9.89-10.72]; P > .99) but was lower than those from chatbot 1 (mean, 12.33 [95% CI, 11.84-12.83]; P < .001) and chatbot 2 (mean, 11.32 [95% CI, 11.05-11.79]; P = .01). Conclusions and Relevance: The findings of this study suggest that chatbots can generate quality, empathetic, and readable responses to patient questions comparable to physician responses sourced from an online forum. Further research is required to assess the scope, process integration, and patient and physician outcomes of chatbot-facilitated interactions.

Telehealth outpatient palliative care in the COVID-19 pandemic: patient experience qualitative study.

OBJECTIVES: Outpatient in-person early palliative care improves quality of life for patients with advanced cancer. The COVID-19 pandemic forced a rapid shift to telehealth visits; however, little is known about how telehealth in outpatient palliative care settings should be optimised beyond the pandemic. We aimed to explore, from the perspective of patients attending an outpatient palliative care clinic, the most appropriate model of care for in-person versus telehealth visits. METHODS: A qualitative study using the grounded theory method. One-on-one, semistructured qualitative interviews were conducted with 26 patients attending an outpatient palliative care clinic at a tertiary cancer centre recruited from two groups: (1) those with >1 in-person appointment prior to 1 March 2020 and >1 telehealth appointment after this date (n=17); and (2) patients who had exclusively telehealth appointments (n=9). Purposive sampling was used to incorporate diverse perspectives. RESULTS: Overall, participants endorsed a flexible hybrid approach incorporating both in-person and telehealth visits. Specific categories were: (1) in-person outpatient palliative care supported building interpersonal connections and trust; (2) telehealth palliative care facilitated greater efficiency, comfort and independence and (3) patient-preferred circumstances for in-person visits (preferred for initial consultations, visits where a physical examination may be required and advance care planning discussions), versus telehealth visits (preferred during periods of relative heath stability). CONCLUSIONS: The elements of in-person and telehealth outpatient palliative care clinic visits described by patients as integral to their care may be used to develop models of hybrid outpatient palliative care delivery beyond the pandemic alongside reimbursement and regulatory guidelines.

Implementation of medication reconciliation in outpatient cancer care.

BACKGROUND: Medication reconciliation (MedRec) is a process where providers work with patients to document and communicate comprehensive medication information by creating a complete medication list (best possible medication history (BPMH)) then reconciling it against what patient is actually taking to identify potential issues such as drug-drug interactions. We undertook an environmental scan of current MedRec practices in outpatient cancer care to inform a quality improvement project at our centre with the aim of 30% of patients having a BPMH or MedRec within 30 days of initiating treatment with systemic therapy. METHODS: We conducted semi-structured interviews with key stakeholders from 21 cancer centres across Canada, probing on current policies, and barriers and facilitators to MedRec. Guided by the findings of the scan, we then undertook a quality improvement project at our cancer centre, comprising six iterative improvement cycles. RESULTS: Most institutions interviewed had a process in place for collecting a BPMH (81%) and targeted patients initiating systemic therapy (59%); however, considerable practice variation was noted and completion of full MedRec was uncommon. Lack of resources, high patient volumes, lack of a common medical record spanning institutions and settings which limits access to medication records from external institutions and community pharmacies were identified as significant barriers. Despite navigating challenges related to the COVID-19 pandemic, we achieved 26.6% of eligible patients with a documented BPMH. However, uptake of full MedRec remained low whereby 4.7% of patients had a documented MedRec. CONCLUSIONS: Realising improvements to completion of MedRec in outpatient cancer care is possible but takes considerable time and iteration as the process is complex. Resource allocation and information sharing remain major barriers which need to be addressed in order to observe meaningful improvements in MedRec.

A Phase II, Open-Label Clinical Trial of Intranasal Ketamine for Depression in Patients with Cancer Receiving Palliative Care (INKeD-PC Study).

Antidepressants require several weeks for the onset of action, a lag time that may exceed life expectancy in palliative care. Ketamine has demonstrated rapid antidepressant effects, but has been minimally studied in cancer and palliative care populations. Herein, the objective was to determine the feasibility, safety, tolerability and preliminary efficacy of intranasal racemic ketamine for major depressive disorder (MDD) in patients with advanced cancer. We conducted a single-arm, open-label phase II trial at the Princess Margaret Cancer Centre in Toronto, ON, Canada. Participants with advanced cancer with moderate to severe MDD received three flexible doses of intranasal (IN) ketamine (50−150 mg) over a one-week period. The primary efficacy outcome was an antidepressant response and remission rates as determined by the Montgomery−Åsberg Depression Rating Scale (MADRS) from baseline to the Day 8 primary endpoint. Twenty participants were enrolled in the trial, receiving at least one dose of IN ketamine, with fifteen participants receiving all three doses. The Day 8 antidepressant response (MADRS decreased by >50%) and remission (MADRS < 10 on Day 8) rates were high at 70% and 45%, respectively. Mean MADRS scores decreased significantly from baseline (mean MADRS of 31, standard deviation 7.6) to Day 8 (11 +/− 7.4) with an overall decrease of 20 points (p < 0.001). Antidepressant effects were partially sustained in the second week in the absence of additional ketamine doses, with a Day 14 mean MADRS score of 14 +/− 9.9. Common adverse effects included fatigue, dissociation, nausea, dysgeusia and headaches; almost all adverse effects were mild and transient, resolving within 2 h of each ketamine dose with one dropout related to adverse effects (negative dissociative episode). Given these promising findings, larger, controlled trials are merited.

Family physicians' involvement in palliative cancer care.

BACKGROUND: Family physicians' (FPs) long-term relationships with their oncology patients position them ideally to provide primary palliative care, yet their involvement is variable. We examined perceptions of FP involvement among outpatients receiving palliative care at a cancer center and identified factors associated with this involvement. METHODS: Patients with advanced cancer attending an oncology palliative care clinic (OPCC) completed a 25-item survey. Eligible patients had seen an FP within 5 years. Binary multivariable logistic regression analyses were conducted to identify factors associated with (1) having seen an FP for palliative care within 6 months, and (2) having a scheduled/planned FP appointment. RESULTS: Of 258 patients, 35.2% (89/253) had seen an FP for palliative care within the preceding 6 months, and 51.2% (130/254) had a scheduled/planned FP appointment. Shorter travel time to FP (odds ratio [OR] = 0.67, 95% confidence interval [CI] = 0.48-0.93, p = 0.02), the FP having a 24-h support service (OR = 1.96, 95% CI = 1.02-3.76, p = 0.04), and a positive perception of FP's care (OR = 1.05, 95% CI = 1.01-1.09, p = 0.01) were associated with having seen the FP for palliative care. English as a first language (OR = 2.90, 95% CI = 1.04-8.11, p = 0.04) and greater ease contacting FP after hours (OR = 1.33, 95% CI = 1.08-1.64, p = 0.008) were positively associated, and female sex of patient (OR = 0.51, 95% CI = 0.30-0.87, p = 0.01) and travel time to FP (OR = 0.66, 95% CI = 0.47-0.93, p = 0.02) negatively associated with having a scheduled/planned FP appointment. Number of OPCC visits was not associated with either outcome. CONCLUSION: Most patients had not seen an FP for palliative care. Accessibility, availability, and equity are important factors to consider when planning interventions to encourage and facilitate access to FPs for palliative care.

Outpatient palliative medicine consultations: urgent or routine?

BACKGROUND: Although outpatient palliative care clinics (OPCCs) provide a venue for early, pre-emptive referral to palliative care on a routine basis, some patients will continue to require urgent referrals. The purpose of this study was to characterise these urgent referrals to determine whether they reflect clinical need or convenience. METHODS: We retrospectively compared new patients in an OPCC who were seen urgently versus those seen at routine appointments. Descriptive statistics compared the two groups in terms of clinical characteristics, referring teams, symptoms, performance status and outcomes. Logistic regression was used to identify factors associated with urgent referral to the OPCC. Overall survival was compared using the log-rank test. RESULTS: Between January 2016 and December 2017, a total of 113 urgent referrals were reviewed in the OPCC; these were compared with a random sample of 217 routine referrals. Patients seen urgently were more likely to be referred by surgical oncology, and to report worse symptom scores for pain (p=0.0007), tiredness (p=0.02), well-being (p=0.001), constipation (p=0.02) and sleep (p=0.01). More patients seen urgently required direct admission to hospital following the visit (17.7% vs 0.9%, p<0.001). Median survival was shorter for patients seen urgently (4.3 months, 95% CI 3.4 to 7.8) versus routinely (8.1 months, 95% CI 7.2 to 9.5). CONCLUSIONS: Compared with routine referrals, new patients seen urgently in the OPCC had higher symptom burden, shorter median survival and a greater chance of direct admission to hospital. Palliative care clinics should consider how best to accommodate urgent referrals.

Palliative medicine outpatient clinic 'no-shows': retrospective review.

OBJECTIVES: Patients who do not attend outpatient palliative care clinic appointments ('no-shows') may have unmet needs and can impact wait times. We aimed to describe the characteristics and outcomes associated with no-shows. METHODS: We retrospectively reviewed new no-show referrals to the Princess Margaret Cancer Centre Oncology Palliative Care Clinic (OPCC) in Toronto, Canada, between January 2017 and December 2018, compared with a random selection of patients who attended their first appointment, in a 1:2 ratio. We collected patient information, symptoms, performance status (Eastern Cooperative Oncology Group (ECOG) and outcomes. Univariable and multivariable logistic regression analyses were used to identify significant factors. RESULTS: Compared with those who attended (n=214), no-shows (n=103), on multivariable analysis, were at higher odds than those who attended of being younger (OR 0.98, 95% CI 0.96 to 1.00, p=0.019), living outside Toronto (OR 2.67, 95% CI 1.54 to 4.62, p<0.001) and having ECOG ≥2 (OR 2.98, 95% CI 1.41 to 6.29, p=0.004). No-shows had a shorter median survival compared with those who attended their first appointment (2.3 vs 8.7 months, p<0.001). CONCLUSION: Compared with patients who attended, no-shows lived further from the OPCC, were younger, and had a poorer ECOG. Strategies such as virtual visits should be explored to reduce no-shows and enable attendance at OPCCs.

Team-based outpatient early palliative care: a complex cancer intervention.

BACKGROUND: Although the effectiveness of early palliative care for patients with advanced cancer has been demonstrated in several trials, there has been no detailed published description of an early palliative care intervention. METHOD: In this paper, we delineate the iterative conception and systematic evaluation of a complex intervention called team-based outpatient early palliative care (TO-EPC), and describe the components of the intervention. The intervention was developed based on palliative care theory, review of previous palliative care interventions and practice guidelines. We conducted feasibility testing and piloting of TO-EPC in a phase 2 trial, followed by evaluation in a large cluster randomised trial and qualitative research with patients and caregivers. The qualitative research informed the iterative refinement of the intervention. RESULTS: Four principles and four domains of care constitute a conceptual framework for TO-EPC. The main domains of care are: coping and support, symptom control, decision-making and future planning. The main principles are that care is flexible, attentive, patient-led and family-centred. The most prominent domain for the initial consultation is coping and support; follow-up visits focus on symptom control, decision-making to maximise quality of life and future planning according to patient readiness. Key tasks are described in relation to each domain. CONCLUSION: The description of our intervention may assist palliative care teams seeking to implement it, researchers wishing to replicate or build on it and oncologists hoping to adapt it for their patients.

Patient-Reported Functional Status in Outpatients With Advanced Cancer: Correlation With Physician-Reported Scores and Survival.

CONTEXT: Performance status measures are increasingly completed by patients in outpatient cancer settings, but are not well validated for this use. OBJECTIVES: We assessed performance of a patient-reported functional status measure (PRFS, based on the Eastern Cooperative Oncology Group [ECOG]), compared with the physician-completed ECOG, in terms of agreement in ratings and prediction of survival. METHODS: Patients and physicians independently completed five-point PRFS (lay version of ECOG) and ECOG measures on first consultation at an oncology palliative care clinic. We assessed agreement between PRFS and ECOG using weighted Kappa statistics, and used linear regression to determine factors associated with the difference between PRFS and ECOG ratings. We used the Kaplan-Meier method to estimate the patients' median survival, categorized by PRFS and ECOG, and assessed predictive accuracy of these measures using the C-statistic. RESULTS: For the 949 patients, there was moderate agreement between PRFS and ECOG (weighted Kappa 0.32; 95% CI: 0.28-0.36). On average, patients' ratings of performance status were worse by 0.31 points (95% CI: 0.25-0.37, P < 0.0001); this tendency was greater for younger patients (P = 0.002) and those with worse symptoms (P < 0.0001). Both PRFS and ECOG scores correlated well with overall survival; the C-statistic was higher for the average of PRFS and ECOG scores (0.619) than when reported individually (0.596 and 0.604, respectively). CONCLUSION: Patients tend to rate their performance status worse than physicians, particularly if they are younger or have greater symptom burden. Prognostic ability of performance status could be improved by using the average of patients and physician scores.

Persistent Diarrhea after Celiac Plexus Block in a Pancreatic Cancer Patient: Case Report and Literature Review.

BACKGROUND: Neurolytic celiac plexus block is increasingly used to treat refractory pain associated with abdominal malignancies, especially pancreatic cancer. While self-limiting diarrhea can occur commonly in patients post procedure, a very rare risk of persistent diarrhea exists. OBJECTIVE: We present a case of a 70 year old female with locally advanced pancreatic adenocarcinoma who was hospitalized for persistent severe diarrhea post celiac plexus block and discuss management options for this adverse effect. DESIGN: A review of the current literature within the past 20 years (PubMed and Ovid databases) was conducted to discuss alternatives of management. MEASUREMENTS/RESULTS: Ninety-three entries were found in total including duplicates and only two were included for relevance. Management options that were discussed included anti-motility agents, alpha-adrenergic agonists, and somastatin analog (octreotide). Our patient was initially treated with loperamide, hyoscine, psyllium, and cholestyramine before responding to octreotide. The patient was discharged on long-acting octreotide after her bowel routine stabilized. CONCLUSIONS: Persistent diarrhea is a very rare complication of celiac plexus block and current literature regarding proper management is based largely on anecdotal evidence. For this patient octreotide was an effective agent for the management of this complication.

Modified Edmonton Symptom Assessment System including constipation and sleep: validation in outpatients with cancer.

CONTEXT: The Edmonton Symptom Assessment System (ESAS) measures the severity of nine symptoms. Constipation and sleep disturbance are common in patients with cancer, but are not currently included in the ESAS. OBJECTIVES: To validate the numerical rating scale (NRS) versions of ESAS and its revised version (ESAS-r), with the additional symptoms of constipation and sleep (CS), and to assess patient preference for either version. METHODS: Outpatients with advanced cancer (N = 202) completed three assessments during a single clinic visit: ESAS-CS, and an added time window of "past 24 hours"; ESAS-r-CS, with a time window of "now" and symptom definitions; and the Memorial Symptom Assessment Scale (MSAS). Internal consistency was calculated using Cronbach's alpha. Paired t-tests compared ESAS-CS and ESAS-r-CS scores; these were correlated with MSAS using Spearman correlation coefficients. Test-retest reliability at 24 hours was assessed in 26 patients. RESULTS: ESAS-CS and ESAS-r-CS total scores correlated well with total MSAS (Spearman's rho 0.62 and 0.64, respectively). Correlation of individual symptoms with MSAS symptoms ranged from 0.54-0.80 for ESAS-CS and 0.52-0.74 for ESAS-r-CS. Although participants preferred the ESAS-r-CS format (42.8% vs. 18.6%) because of greater clarity and understandability, the "past 24 hours" time window (52.8%) was favored over "now" (21.3%). Shortness of breath and nausea correlated better for the "past 24 hours" time window (0.8 and 0.72 vs. 0.74 and 0.64 in ESAS-r-CS, respectively). The 24-hour test-retest of the ESAS-CS demonstrated acceptable reliability (intraclass correlation coefficient = 0.69). CONCLUSION: The ESAS-CS and ESAS-r-CS NRS versions are valid and reliable for measuring symptoms in this population of outpatients with advanced cancer. Although the ESAS-r-CS was preferred, patients favored the 24-hour time window of the ESAS-CS, which also may best characterize fluctuating symptoms.

Simple prognostic model for patients with advanced cancer based on performance status.

PURPOSE: Providing survival estimates is important for decision making in oncology care. The purpose of this study was to provide survival estimates for outpatients with advanced cancer, using the Eastern Cooperative Oncology Group (ECOG), Palliative Performance Scale (PPS), and Karnofsky Performance Status (KPS) scales, and to compare their ability to predict survival. METHODS: ECOG, PPS, and KPS were completed by physicians for each new patient attending the Princess Margaret Cancer Centre outpatient Oncology Palliative Care Clinic (OPCC) from April 2007 to February 2010. Survival analysis was performed using the Kaplan-Meier method. The log-rank test for trend was employed to test for differences in survival curves for each level of performance status (PS), and the concordance index (C-statistic) was used to test the predictive discriminatory ability of each PS measure. RESULTS: Measures were completed for 1,655 patients. PS delineated survival well for all three scales according to the log-rank test for trend (P < .001). Survival was approximately halved for each worsening performance level. Median survival times, in days, for each ECOG level were: EGOG 0, 293; ECOG 1, 197; ECOG 2, 104; ECOG 3, 55; and ECOG 4, 25.5. Median survival times, in days, for PPS (and KPS) were: PPS/KPS 80-100, 221 (215); PPS/KPS 60 to 70, 115 (119); PPS/KPS 40 to 50, 51 (49); PPS/KPS 10 to 30, 22 (29). The C-statistic was similar for all three scales and ranged from 0.63 to 0.64. CONCLUSION: We present a simple tool that uses PS alone to prognosticate in advanced cancer, and has similar discriminatory ability to more complex models.

Addition of methadone to another opioid in the management of moderate to severe cancer pain: a case series.

BACKGROUND: Previous research has reported improved pain after adding methadone to another opioid, but did not quantify this benefit using a validated outcome measure. OBJECTIVE: To assess quantitatively the effectiveness of adding methadone to another opioid for moderate to severe cancer-related pain. DESIGN: All outpatients attending the Oncology Palliative Care Clinic from September 2010-September 2011, who had received methadone, were identified from pharmacy records. Inclusion criteria included: histological diagnosis of malignancy, age >18 years, taking regular opioids and Edmonton Symptom Assessment System (ESAS) pain score ≥ 4. MEASUREMENT: The primary outcome measure was a decrease in pain score of ≥ 2 points from methadone initiation to one-month follow-up (or closest available ESAS). RESULTS: Twenty patients were available for analysis, 16 of whom had neuropathic pain (80%). Eight patients (40%) had a decrease in pain score of ≥ 2 points at 1 month and a further 7 (35%) had a decrease of ≥ 2 points at the closest available time point. The mean pain score decreased from 7.7 +/- 1.8 to 5.2 +/- 2.4 from time of initiation to time of evaluation. The mean daily routine morphine equivalent, (excluding methadone), was 338 +/- 217.8 mg/day at initiation and 332 +/- 191 mg/day at evaluation; for methadone, mean doses at initiation and evaluation were 4.4 +/- 1.4 mg/day and 15.5 +/- 5.9 mg/day, respectively. Methadone was well tolerated in 17 patients (85%). CONCLUSIONS: The addition of methadone was associated with improved pain control for patients with moderate to severe pain on another opioid and appears to offer a safe, well-tolerated and practical alternative in this situation.

Impact of an oncology palliative care clinic on access to home care services.

Home care (HC) is important for patients with cancer as performance status declines. Our study of 1224 patients at a Canadian cancer center examined the impact of an oncology palliative care clinic (OPCC) on HC referral. The HC referral frequency was calculated before and after the first OPCC consultation, in total and according to performance status (Palliative Performance Scale, PPS). Characteristics associated with HC referral were investigated. After the first OPCC consultation, there was an increase in HC referral from 39% (477 of 1224; 49% of those with PPS ≤60) to 69% (841 of 1224; 88% of those with PPS ≤60). Factors independently associated with HC referral were poor PPS (P < .001) and older age (P = .003). Thus OPCC involvement resulted in markedly increased HC referrals, particularly for older patients with poor performance status.

Vascular binding, blood flow, transporter, and enzyme interactions on the processing of digoxin in rat liver.

The roles of vascular binding, flow, transporters, and enzymes as determinants of the clearance of digoxin were examined in the rat liver. Digoxin is metabolized by Cyp3a and utilizes the organic anion transporting polypeptide 2 (Oatp2) and P-glycoprotein (Pgp) for influx and excretion, respectively. Uptake of digoxin was found to be similar among rat periportal (PP) and perivenous (PV) hepatocytes isolated by the digitonin-collagenase method. The Km values for uptake were 180 +/- 112 and 390 +/- 406 nM, Vmax values were 13 +/- 8 and 18 +/- 4.9 pmol/min/mg protein, and nonsaturable components were 9.2 +/- 1.3 and 10.7 +/- 2.5 microl/min/mg for PP and PV, respectively. The evenness of distribution of Oatp2 and Pgp was confirmed by Western blotting and confocal immunofluorescent microscopy. When digoxin was recirculated to the rat liver preparation in Krebs-Henseleit bicarbonate (KHB) for 3 h in absence or presence of 1% bovine serum albumin (BSA) and 20% red blood cell (rbc) at flow rates of 40 and 10 ml/min, respectively, biexponential decays were observed. Fitted results based on compartmental analyses revealed a higher clearance (0.244 +/- 0.082 ml/min/g) for KHB-perfused livers over the rbc-albumin-perfused livers (0.114 +/- 0.057 ml/min/g) (P < 0.05). We further found that binding of digoxin to 1% BSA was modest (unbound fraction = 0.64), whereas binding to rbc was associated with slow on (0.468 +/- 0.021 min(-1)) and off (1.81 +/- 0.12 min(-1)) rate constants. We then used a zonal, physiologically based pharmacokinetic model to show that the difference in digoxin clearance was attributed to binding to BSA and rbc and not to the difference in flow rate and that clearance was unaffected by transporter or enzyme heterogeneity.