Can P-glycoprotein expression on malignant tumor tissues predict opioid transport at the blood-brain barrier in cancer patients?

Wang et al. investigated the analgesic effects of morphine and buprenorphine in patients with histologically confirmed malignant tumors of different kinds at terminal stages in one palliative care unit [12]. They showed that patients with P-glycoprotein (P-gp)+ tumors required a higher morphine dose to achieve a satisfactory analgesic effect assessed using the visual analog scale test, in comparison to patients with P-gp– tumors. Following the infusion of higher morphine amounts, patients with P-gp+ tumors achieved adequate analgesia. In contrast, patients exhibited similar analgesic responses to buprenorphine, regardless of their tumor’s P-gp expression. P-gp is a well-known ATP-binding cassette transporter, encoded by the MDR1 (ABCB1) gene in humans. P-gp is expressed in a variety of normal tissues, mostly of epithelial origin, including at the luminal membrane of brain capillary endothelial cells composing the blood-brain barrier (BBB) and restricting brain parenchyma distribution of its substrates by unidirectional efflux [9]. In Wang’s work [12], differences in the analgesic response to morphine between patients with P-gp+ and P-gp– tumors were attributed to the P-gp-controlled amounts of morphine reaching the brain across the BBB. Consistently, P-gp is highly involved in the transport of the majority of opioids at the BBB. As acknowledged by the authors, morphine is a well-known P-gp substrate, assessed in vitro and in vivo, either in animals or in humans. In contrast, buprenorphine is not a P-gp substrate as recently demonstrated in vitro using human P-gptransfected cells [10] or placenta [7] and in vivo in mice [2, 5], although one study suggested a possible P-gp contribution to buprenorphine brain-to-blood efflux in vivo in the rat [8]. Opioids are potent centrally acting analgesics; however, the role of the increasingly recognized peripheral opioid receptor system in the observed difference in response to morphine between Wang’s patients with P-gp+ and P-gp– tumors cannot be ruled out. Nevertheless, at the tumor level, the exact role of P-gp in limiting morphine accessibility to its receptors remains to be determined. P-gp over-expression or up-regulation has been recognized as contributing to the development of resistance to chemotherapy in malignancies. Based on their findings, Wang et al. stated that P-gp expression in tumors may also be a valuable biomarker to predict the individual analgesic response to morphine, assuming its ability to predict morphine transport at the BBB [12]. Prediction of the patient’s response to P-gp-transported opioids and individualization of drug therapy appears extremely interesting, especially if simple tests become available for an easy screening